Cutaneous melanoma

Abstract Cutaneous melanoma is a malignancy arising from melanocytes of the skin. Incidence rates are rising, particularly in White populations. Cutaneous melanoma is typically driven by exposure to ultraviolet radiation from natural sunlight and indoor tanning, although there are several subtypes that are not related to ultraviolet radiation exposure. Primary melanomas are often darkly pigmented, but can be amelanotic, with diagnosis based on a combination of clinical and histopathological findings. Primary melanoma is treated with wide excision, with margins determined by tumour thickness. Further treatment depends on the disease stage (following histopathological examination and, where appropriate, sentinel lymph node [...]

July 24th, 2023|Comments Off on Cutaneous melanoma

The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

Abstract Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy resistance. Here we show that resistance programs include (1) the loss of wild-type antigen expression, resulting from tumor-intrinsic IFNγ signaling and melanoma de-differentiation, (2) the disruption of antigen presentation via multiple independent mechanisms affecting MHC [...]

March 18th, 2023|Comments Off on The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

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 [...]

March 15th, 2023|Comments Off on IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.

Efficacy of ipilimumab 3mn/kg following progression on low-dose ipilimumab in metastatic melanoma.

Abstract Background: Differing doses of ipilimumab (IPI) are used in combination with an anti-PD1 antibody in advanced melanoma. There is no data on the outcomes of patients who progress following low-dose IPI (< 3 mg/kg) and are subsequently treated with IPI 3 mg/kg (IPI3). We conducted a multicentre retrospective survey to assess the efficacy of this strategy. Methods: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3 mg/kg) with an anti-PD1 antibody with recurrence (neo/adjuvant) or progressive disease (metastatic), who then received IPI3± anti-PD1 antibody were eligible. Best investigator-determined Response [...]

March 11th, 2023|Comments Off on Efficacy of ipilimumab 3mn/kg following progression on low-dose ipilimumab in metastatic melanoma.

Challenges in oncology career: are we closing the gender gap? Results of the new ESMO Women for Oncology Committee survey.

Abstract Background: Following a European Society for Medical Oncology Women for Oncology (ESMO W4O) survey in 2016 showing severe under-representation of female oncologists in leadership roles, ESMO launched a series of initiatives to address obstacles to gender equity. A follow-up survey in October 2021 investigated progress achieved. Materials and methods: The W4O questionnaire 2021 expanded on the 2016 survey, with additional questions on the impact of ethnicity, sexual orientation and religion on career development. Results were analysed according to respondent gender and age. Results: The survey sample was larger than in 2016 (n = 1473 versus 482), especially among [...]

February 24th, 2023|Comments Off on Challenges in oncology career: are we closing the gender gap? Results of the new ESMO Women for Oncology Committee survey.

Case series: Immune checkpoint inhibitor-induced transverse myelitis.

Abstract Introduction: Increasing implementation of the highly efficacious immune checkpoint inhibitors (ICIs) has raised awareness of their various complications in the form of immune-related adverse events (irAEs). Transverse myelitis following ICIs is thought to be a rare but serious neurologic irAE and knowledge is limited about this distinct clinical entity. Cases: We describe four patients across three tertiary centers in Australia with ICI-induced transverse myelitis. Three patients had a diagnosis of stage III–IV melanoma treated with nivolumab and one patient had stage IV non-small cell lung cancer treated with pembrolizumab. All patients had longitudinally extensive transverse myelitis on magnetic [...]

February 21st, 2023|Comments Off on Case series: Immune checkpoint inhibitor-induced transverse myelitis.

Intratumoral CD16+ macrophages are associated with clinical outcomes of patients with metastatic melanoma treated with combination anti-PD-1 and anti-CTLA-4 therapy.

Abstract Purpose: This study characterizes intratumoural macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16) expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex immunohistochemistry in relation to treatment outcomes. Results: Patients who responded to combination ICI contained higher CD16+ macrophage densities than those who did not respond (196 vs 7 cells/mm2; p [...]

February 15th, 2023|Comments Off on Intratumoral CD16+ macrophages are associated with clinical outcomes of patients with metastatic melanoma treated with combination anti-PD-1 and anti-CTLA-4 therapy.

Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.

Abstract Background: In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma [...]

February 11th, 2023|Comments Off on Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.

IFNγ signaling sensitizes melanoma cells to BH3 Mimetics.

Abstract Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor–based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and [...]

February 1st, 2023|Comments Off on IFNγ signaling sensitizes melanoma cells to BH3 Mimetics.

Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation.

Abstract Background: Metastatic Merkel cell carcinoma (mMCC) is highly responsive to immune checkpoint inhibitors (ICIs); however, durability of response after treatment cessation and response to retreatment in the setting of progression is unknown. Methods: Patients (pts) having mMCC from 10 centres who discontinued ICI treatment for a reason other than progression were studied. Results: Forty patients were included. Median time on treatment was 13.5 months (range 1-35). Thirty-one patients (77.5%) stopped treatment electively while 9 patients (22.5%) stopped due to treatment-related toxicity. After median of 12.3 months from discontinuation, 14 pts (35%) have progressed (PD). Disease progression rate following [...]

January 28th, 2023|Comments Off on Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation.
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