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Introduction Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. Methods & results Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor–pretreated compared with MAPK-inhibitor–naive intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. Conclusion The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. Patients and methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression. Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC)

Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Radiotherapy has become an effective treatment in the management of melanoma patients. It has its place beneath surgical treatment options in a tumor entity that has only limited response to systemic medical therapies. New therapies, such as ipilimumab and vemurafenib, may prolong survival for several months but will cure only a few patients. Radiotherapy will still be required in adjuvant settings to reduce the local recurrence rate and in palliative situations, particularly in brain and bone metastasis. We review several indications for radiotherapy in the management of malignant melanoma with an effect on the guidelines in our clinical practice.

The ongoing increase in melanoma incidence throughout Caucasian populations worldwide raises the question of an economic and efficient management of primary melanoma and follow-up. The primary treatment of a cutaneous melanoma is surgical excision. An excision biopsy is recommended, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for a higher tumor thickness should be applied at the primary excision or in a two-step procedure. When dealing with facial, acral, or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. Whereas the treatment for primary melanoma is accepted world wide, follow-up strategies for melanoma patients are discussed controversially, and so far, no international consensus has been reached.

Melanoma is highly resistant to chemotherapy. In melanoma, the PI3K-AKT-mTOR signaling pathway is constitutively activated through multiple mechanisms. Several experimental studies suggest that targeting the PI3K-AKT-mTOR signaling pathway is a promising strategy to overcome chemoresistance. This is the first report describing a chemosensitizing effect of mTOR inhibition in patients with melanoma. We report two cases of patients with metastatic melanoma who showed significant remission after combination of carboplatin and paclitaxel with the mTOR inhibitor sirolimus. Our case report, together with the literature discussed, suggests that mTOR inhibition possibly enhances the sensitivity of melanoma cells to chemotherapy and should prompt in-depth and clinical investigation.

Facing the increasing number of melanoma patients is the controversial question of whether an incisional biopsy is associated with an unfavorable patient prognosis. Results of nine studies that occurred during the last four decades were reviewed. One of these studies was a large, prospective randomized controlled trial. Evidence from this trial and from most other studies is that incisional biopsies were not associated with an unfavorable prognosis for melanoma patients. Incisional biopsies are currently recommended for the histopathologic diagnosis of large tumors in facial, mucosal, and acral locations. Complete excisional biopsies are the generally recommended standard for melanoma surgery. Incisional biopsies of malignant melanoma do not negatively influence prognosis. Complete excision of primary melanoma is still the recommended standard of care and is a precondition for accurate histopathologic diagnosis.