Scolyer, Richard

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

Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors

Abstract The gut microbiota modulates immune processes both locally and systemically. This includes whether and how the immune system reacts to emerging tumours, whether antitumour immune responses are reactivated during treatment with immune-checkpoint inhibitors (ICIs), and whether unintended destructive immune pathologies accompany such treatment. Advances over the past decade have established that the gut microbiota is a promising target and that modulation of the microbiota might overcome resistance to ICIs and/or improve the safety of treatment. However, the specific mechanisms through which the microbiota modulates antitumour immunity remain unclear. Understanding the biology underpinning microbial associations with clinical outcomes in [...]

July 24th, 2023|Comments Off on Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors

Junctional Nevus and Early Melanoma on Sun-Damaged Skin of the Head/Neck: a Clinico-Pathologic Challenge.

Abstract Introduction: Melanoma on the head/neck area can show subtle clinical, dermoscopic and histologic features at early stages, being difficult to differentiate from junctional nevi. Objectives: This case series aims to raise awareness on the topic of misdiagnosis of early lentigo maligna as junctional nevi. Methods: From the databases of three pigmented lesion clinics in Italy, Australia, and France, we retrieved all cases of lesions of the head/neck area with an initial histopathologic diagnosis of junctional nevus (JN) or dysplastic junctional nevus (DJN) which subsequently recurred and were ultimately diagnosed as melanoma. Moreover, we also retrieved those cases with [...]

March 22nd, 2023|Comments Off on Junctional Nevus and Early Melanoma on Sun-Damaged Skin of the Head/Neck: a Clinico-Pathologic Challenge.

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.

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

Abstract Background: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation–induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. Methods: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg [...]

March 2nd, 2023|Comments Off on Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

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 [...]

February 28th, 2023|Comments Off on In vivo reflectance confocal microscopy can detect the invasive component of lentigo maligna melanoma: Prospective analysis and case-control study.
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