Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma
Abstract Background: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. Patients and methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), [...]
Neoadjuvant Triplet Immune Checkpoint Blockade in Newly Diagnosed Glioblastoma.
Abstract Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront [...]
Inter-rater concordance of basal cell carcinoma subtypes: influences on reporting format and opportunities for further classification modifications.
Abstract 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 [...]
IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.
Abstract Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab [...]
In vivo reflectance confocal microscopy can detect the invasive component of lentigo maligna melanoma: Prospective analysis and case-control study.
Abstract Background: Lentigo maligna (LM), a form of melanoma in situ, has no risk of causing metastasis unless dermal invasive melanoma (LMM) supervenes. Furthermore, the detection of invasion impacts prognosis and management. Objective: To assess the accuracy of RCM for the detection of invasion component on LM/LMM lesions. Methods: In the initial case-control study, the performance of one expert in detecting LMM at the time of initial RCM assessment of LM/LMM lesions was recorded prospectively (n = 229). The cases were assessed on RCM-histopathology correlation sessions and a panel with nine RCM features was proposed to identify LMM, which [...]
Representativeness of initial skin biopsies showing pure desmoplastic melanoma: implications for management
Abstract Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is ≥90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but [...]
Melanomas in children and adolescents: clinicopathologic features and survival outcomes.
Abstract Background: Melanomas in the first 2 decades of life are uncommon and poorly understood. Objective: To assess clinicopathologic features and survival of children (≤11 years) and adolescents (12-19 years) diagnosed with melanoma. Methods: A pooled cohort of 514 patients was analyzed (397 Dutch, 117 Australian; 62 children, 452 adolescents). Pathology reports were reevaluated to determine melanoma subtypes. Multivariable Cox models were generated for recurrence-free survival (RFS) and overall survival (OS). Results: Melanoma subtypes were conventional melanoma (superficial spreading, nodular, desmoplastic, and acral lentiginous), spitzoid melanoma, and melanoma associated with a congenital nevus in 428, 78, and 8 patients, respectively. Ten-year RFS was [...]
Metastasizing and non-metastasizing thick melanoma: clinicopathological predictors and molecular profiling.
Abstract Background. Cutaneous melanoma (CM) is the most aggressive form of skin cancer and its worldwide incidence rises faster than that of any other cancer (1). Early stages can successfully be treated by surgery, but once metastasis has occurred, the prognosis is infaust. Prognosis can be predicted on the basis of the stage of the patient and depends on a number of clinicopathological parameters, including thickness and ulceration of the primary melanoma (2). However, some 5-10% of thick (≥2mm) melanomas do not follow this scenario and run an unpredictable course. In our earlier study on thick primary melanomas (≥2mm) [...]
Comparative genomics provides etiological and biological insights into melanoma subtypes
Abstract Background: Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy. Methods: Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic [...]
Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites.
Abstract Background: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases. Methods: We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV [...]