Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients-The European MelSkinTox study.

BACKGROUND: Checkpoint inhibitors provide an effective approach for the melanoma treatment. They prolong lymphocyte effects, which explains the cytotoxicity underlying immune-related adverse events (IrAEs). Cutaneous IrAEs affect nearly 40% of PD-1i and 50% of CTLA4i-treated patients. Severe cutaneous irAE do not often occur but could be life-threatening and may persist despite treatment discontinuation. METHODS: We aimed to investigate cutaneous IrAEs in a cohort of patients treated with ICI across Europe in an effort to characterize the reactions in a real-world, phase IV, post-marketing study using a follow-up questionnaire. Data since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow-up of melanoma and cutaneous adverse events, supported by EADO. The dermatoses reported were pooled into four categories: inflammatory dermatosis, bullous diseases, drug-related eruptions and pigmentary diseases. RESULTS: Inflammatory benign dermatoses (n = 63) represented the most common group of reactions (52.5%), followed by drug-related eruptions (n = 24, 20%), pigmentary diseases (n = 23, 19.2%) and bullous diseases (n = 10, 8.3%). Grade II (n = 41, 34.2%) are represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis-like rash, urticarial eruption and vitiligo. Grade III (n = 18, 15.0%) are represented by bullous pemphigoid, lichenoid eruption and rashes. Grade IV (n = 2, 1.7%) is only represented by bullous disease. Most cutaneous IrAEs led to immunotherapy continuation (n = 95, 88.0%). CR is associated with more severe the cutaneous irAEs. We report an average time-to-onset of 208 days and some late-onset events. CONCLUSION: Our study has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. Grade I-II cutaneous IrAE are easily managed allowing ongoing anticancer treatment. Severe late-onset cutaneous irAE are not uncommon. A dermatological follow-up helps mitigate the risk of life-threatening adverse events. These findings highlight the importance of oncodermatological involvement in management of patients with melanoma receiving immunotherapy.

Prognostic factors in 161 patients with mucosal melanoma: a study of German Central Malignant Melanoma Registry.

BACKGROUND: Mucosal melanoma is a rare malignancy which represents approximately 1% of all melanomas. It is shown that mucosal melanomas have a different biology and less favourable prognosis than its cutaneous counterpart. OBJECTIVES: Predictive and prognostic factors of survival for mucosal melanoma have not yet been elucidated. The aim of this study was to investigate risk factors affecting the course of mucosal melanoma patients followed in our clinic. METHODS: One hundred and sixty-one patients with mucosal melanoma prospectively documented in the German Central Malignant Melanoma Registry (CMMR) were included in this study. Gender, age, localization, stage at first medical examination, tumour thickness and mutational status were documented. The American Joint Committee on Cancer (AJCC), 7th edition was used to define tumour stage. Kaplan-Meier survival curves were evaluated compared with the log-rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors. RESULTS: According to the localization, patients were categorized in 44.7% oral-nasal, 28.6% genital, 20.5% anorectal and 6.2% visceral. Genital mucosal melanomas had the most favourable 5-year OS rate (58.6%) followed by visceral (58.3%) and oral-nasal (39.3%). Anorectal melanomas had the worst OS time (median: 21 ± 4.8 months) and 5-year survival rate (22.7%). Patients <60 years had a better survival than the older group (P = 0.013). Tumour stage at the time of the first medical examination was also a significant factor for survival (P = 0.001). Gender and mutational status were found to have no effect on survival. Age (<60 years vs. ≥60 years; HR = 2.1) and stage at first medical examination (Stage I vs. Stage IV; HR = 8.2) are shown to be significant independent prognostic factors on multivariate Cox regression analysis, but not localization. CONCLUSION: In this study, we observed that older age and advanced stage have significant negative effects on the survival of mucosal melanoma. Thus, the AJCC staging system is applicable for mucosal melanoma.

Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

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-naïve 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.

Diagnostic accuracy of dermatofluoroscopy in cutaneous melanoma detection: results of a prospective multicentre clinical study in 476 pigmented lesions.

BACKGROUND: Early detection is a key factor in improving survival from melanoma. Today, the clinical diagnosis of cutaneous melanoma is based mostly on visual inspection and dermoscopy. Preclinical studies in freshly excised or paraffin-embedded tissue have shown that the melanin fluorescence spectra after stepwise two-photon excitation, a process termed dermatofluoroscopy, differ between cutaneous melanoma and melanocytic naevi. However, confirmation from a larger prospective clinical study is lacking. OBJECTIVES: The primary end point of this study was to determine the diagnostic accuracy of dermatofluoroscopy in melanoma detection. Secondary end points included the collection of data for improving the computer algorithm that classifies skin lesions based on melanin fluorescence and the assessment of safety aspects. METHODS: This was a prospective, blinded, multicentre clinical study in patients with pigmented skin lesions (PSLs) indicated for excision either to rule out or to confirm cutaneous melanoma. All included lesions underwent dermoscopy and dermatofluoroscopy in vivo before lesions were excised and subjected to histopathological examination. RESULTS: In total, 369 patients and 476 PSLs were included in the final analysis. In 101 of 476 lesions (21·2%) histopathology revealed melanoma. The observed sensitivity of dermatofluoroscopy was 89·1% (90 of 101 melanomas identified), with an observed specificity of 44·8%. The positive and negative predictive values were 30·3% and 93·9%, respectively. No adverse events occurred. CONCLUSIONS: Dermatofluoroscopy is a safe and accurate diagnostic method to aid physicians in diagnosing cutaneous melanoma. Limitations arise from largely amelanotic or regressing lesions lacking sufficient melanin fluorescence.

Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients.

BACKGROUND: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism. METHODS: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation. RESULTS: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. CONCLUSION: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.

[Stripping operations of the parva and magna saphenous veins. Long-term study in relation to pre- and postoperative dysfunction]. / Strippingoperationen der V. saphena magna und parva. Langzeituntersuchung in Beziehung zu prä- und postoperativen Funktionsprüfungen.

BACKGROUND AND OBJECTIVE: Little data is available on the log-term effects of stripping the greater and lesser saphenous veins in combination with pre- and post-operative function tests. The goal of this study was to record the long-term course after surgery based on the function data. PATIENTS/METHODS: Drain-off capability was measured preoperatively and postoperatively by light reflection rheography in 203 patients (58 men, 145 women) between 17 and 79 years. Questionnaires were used about 9 years after surgery to determine the nature of the post-operative complaints. RESULTS: Nine years after surgery 58% of the patients still had no discomfort, and 78% had fewer problems with venous ulcers. About 60% reported improvement of swelling and skin changes. The results tended to be better in men. Freedom of complaints was longer-lasting where venous drainage had been good before surgery. CONCLUSIONS: Stripping operations can produce long-lasting improvement of venous ulceration and the above-mentioned complaints in a high percentage of patients.