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BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).
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Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF+SPARCL1+ and CENPF+ melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.
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Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Melanoma , Análise de Célula Única , Microambiente Tumoral , Microambiente Tumoral/imunologia , Humanos , Imunoterapia/métodos , Melanoma/terapia , Melanoma/imunologia , Melanoma/patologia , MultiômicaRESUMO
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.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Austrália , Biomarcadores Tumorais/genética , Biópsia de Linfonodo SentinelaRESUMO
Diagnosis of basal cell carcinoma (BCC) higher risk subtypes influences management strategies because of their propensity to recur locally. Subtyping is prone to inter-observer variability, and subtyping definitions are inconsistently applied. This study sought to compare the interobserver reproducibility of individual BCC subtypes using the 4th edition World Health Organization (WHO) Classification of Skin Tumours (CoST) definitions, with classification into lower and higher risk histological subtype groups. Ninety-one BCC cases were rated by seven pathologists, noting the presence of BCC subtype(s), and providing a higher or lower risk subtype grouping per case. Raters were provided with definitions as per the 4th edition WHO CoST for 10 listed BCC subtypes. Surgical specimen type was noted. Subgroup analysis was performed to exclude cases when the tumour deep front was not well visualised, or there was tangential sectioning (n = 6). Light's kappa was used to assess inter-rater reliability. From the total group (n = 91), five BCC subtypes showed a sufficient number of ratings for computing a κ statistic. From these five subtypes, superficial subtype showed substantial inter-rater agreement (κ = 0.64), and the other four subtypes showed moderate inter-rater agreement [nodular (κ = 0.45), sclerosing/morphoeic (κ = 0.45), infiltrating (κ = 0.49) and micronodular (κ = 0.57)]. Two-tiered rating into either higher or lower risk subtype showed substantial inter-rater agreement (κ = 0.72). Our results suggest a need to more precisely define BCC subtypes. We suggest reporting BCC subtype using a two-tiered risk grouping, followed by specific subtypes present. Further studies examining the inter-rater reliability of less common BCC subtypes are required.
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Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/patologia , Reprodutibilidade dos Testes , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/patologia , Variações Dependentes do ObservadorRESUMO
Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.
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Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases/genética , Proteínas Hedgehog , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Neoplasias Cutâneas/patologia , GenômicaRESUMO
Acquired and congenital melanocytic naevi are common benign neoplasms. Understanding their biology and genetics will help clinicians and pathologists correctly diagnose melanocytic tumours, and generate insights into naevus aetiology and melanomagenesis. Genomic data from published studies analysing acquired and congenital melanocytic naevi, including oncogenic driver mutations, common melanoma associated mutations, copy number aberrations, somatic mutation signature patterns, methylation profile, and single nucleotide polymorphisms, were reviewed. Correlation of genomic changes to dermoscopic features, particular anatomic sites and total body naevus counts, was also performed. This review also highlights current scientific theories and evidence concerning naevi growth arrest. Acquired and congenital melanocytic naevi show simple genomes, typically characterised by mutually exclusive single oncogenic driver mutations in either BRAF or NRAS genes. Genomic differences exist between acquired and congenital naevi, common and dysplastic naevi, and by dermoscopic features. Acquired naevi show a higher rate of BRAF hotspot mutations and a lower rate of NRAS hotspot mutations compared to congenital naevi. Dysplastic naevi show upregulation of follicular keratinocyte-related genes compared to common naevi. Anatomical locations and DNA signatures of naevi implicates ultraviolet radiation and non-ultraviolet radiation pathways in naevogenesis. DNA driver point mutations in acquired and congenital melanocytic naevi have been well characterised. Future research is required to better understand transcriptional and epigenetic changes in naevi, as well as those regulating naevus growth arrest and cell environment signalling.
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Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Humanos , Síndrome do Nevo Displásico/genética , Síndrome do Nevo Displásico/patologia , Genômica , Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
OBJECTIVE: To improve prebiopsy diagnostic accuracy and surgical management of pigmented appearing lesions on the lips, particularly melanoma, using in vivo reflectance confocal microscopy (RCM). STUDY DESIGN: Prospective case series over a 12-month period between 2015 and 2016. The setting was two specialist dermatology referral centers with expertise in confocal microscopy. The study population was a consecutive sample of patients with pigmentation of the lip for which the cause was uncertain clinically, whose differential diagnosis included melanoma, and who had undergone both in vivo RCM and subsequent biopsy. The outcome measures were RCM features, dermoscopy features, and histopathological diagnosis. Results were reported by descriptive analysis and correlations made between RCM features and histopathology. RESULTS: Eight patients were recruited for the study. In vivo RCM facilitated the targeting of small biopsies to identify two in situ oral melanoma recurrences and successfully mapped an in situ oral melanoma before wide excision. Suprabasal dendritic pagetoid cells and epidermal disarray on RCM were useful indicators for in situ melanoma of the lip. Previously described dermoscopy features for mucosal melanoma were not very helpful in diagnosing melanoma in our series. Challenges included evaluating inflamed lesions with pigment incontinence. CONCLUSIONS: RCM can assist in the diagnosis and management of pigmented lip lesions, but additional studies are required to further evaluate these initial observations.
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Neoplasias Labiais/diagnóstico , Melanoma/diagnóstico , Microscopia Confocal/instrumentação , Adulto , Idoso , Biópsia , Dermoscopia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: A negative sentinel lymph node biopsy (SLNB) from patients with head and neck Merkel cell carcinoma (HNMCC) may allow the patient to avoid further adjunctive therapies. However, there is considerable regional variability of lymphatic drainage from primary sites involving the head and neck, and Merkel cell carcinoma (MCC) has aggressive biologic behavior. OBJECTIVE: The primary aim of this systematic review was to document the incidence of regional recurrence and mortality from HNMCC patients after a negative SLNB. METHODS: A systematic search of the English literature was conducted via Ovid Medline and Embase from inception until 2013 and the Cochrane Central Register of Controlled Trials from 1991 to January 2014. RESULTS: Twenty-three studies, with a total of 81 patients matched the inclusion criteria. The incidence of regional recurrence from the entire cohort was 12.3%, and there was a 5% mortality rate. The mean follow-up time, excluding the 30 patients who did not have individual follow-up times specified, was 32.8 months. LIMITATIONS: This review included studies had variable follow-up durations and treatments for MCC. CONCLUSIONS: Despite negative pathologic staging of the neck using SLNB in HNMCC patients, there is still a high incidence of regional recurrence and mortality, over a short follow-up period.