Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing. FINDINGS: Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment. INTERPRETATION: Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease. FUNDING: Bristol-Myers Squibb.

Sebaceous tumours: more than skin deep.

CLINICAL PRESENTATION: A 77-year-old man presented to our skin cancer centre with various cutaneous tumours occurring in 2006-2017. Histopathology showed a 'hidradenocarcinoma' on the left upper back (2006) and a sebaceous adenoma (figure 1) on the left shoulder (2011). In 2017, he developed a sebaceous carcinoma on the middle upper back, which manifested as a slowly enlarging, asymptomatic nodule. Medical history was significant for curative resection of colorectal cancer in 1988.gutjnl;67/11/1957/F1F1F1Figure 1Clinical appearance of the sebaceous adenoma on the patient's left shoulder in 2011.The most recent lesion was subjected to extensive immunohistochemical assessment. The neoplastic cells were positive for cytokeratin 5/6, cytokeratin 7, cluster of differentiation antigen 10, adipophilin, androgen receptor, epithelial membrane antigen, KI67 antigen, MLH1 and PMS2, but stained negative for gross cystic disease fluid protein 15, prostate-specific antigen, carbohydrate antigen 19/9, CDX2 protein, hepatocyte-specific antigen, carcinoembryonic antigen, cluster of differentiation antigen 117 and cytokeratin 19. Given the variety of histological manifestations of the patient's skin neoplasms, further studies were performed. They revealed positive nuclear expression signals for MLH1, MSH6 and PMS2, whereas MSH2 expression was absent in almost all tumour cells (figure 2). Positron emission tomography (PET)/CT and colonoscopy did not detect any pathological findings. However, molecular genetic analysis of peripheral blood showed a heterozygous deletion of exon 7 of the MSH2 gene. Subsequently, several family members tested positive for MSH2 mutations and underwent genetic counselling.gutjnl;67/11/1957/F2F2F2Figure 2(A-D) Histopathological images of the patient's most recent lesion (diaminobenzidine, original magnification, ×100). The tumour cells demonstrated strong nuclear positivity for MLH1 (A) and PMS2 (B), but were essentially negative for MSH6 (C) and MSH2 (D). QUESTION: What is your diagnosis? DIAGNOSIS: Muir-Torre syndrome (MTS).

Maspin expression in the invasive margin of primary melanomas may reflect an aggressive tumor phenotype.

BACKGROUND: The role of maspin has been discussed controversially in different tumors. In the majority of malignant tumors, maspin seems to act as a tumor suppressor. However, data about maspin expression as well as its function in melanoma are very inconsistent. OBJECTIVE: To investigate the expression of maspin in melanomas and to correlate the intensity of maspin staining with prognostic parameters of the tumor and with progression-free and overall survival. PATIENTS AND METHODS: Primary melanomas from 47 patients were investigated for maspin expression using immunohistochemistry. RESULTS: Maspin was heterogeneously expressed predominantly in the cytoplasm of melanoma cells. Maspin staining intensity in the invasive part of the tumor correlated with parameters of prognosis such as Clark level (p  =  0.05), tumor thickness (p  =  0.002) and stage of disease (p  =  0.023). Maspin staining intensity in the invasive front of the tumor significantly correlated with death from disease (p  =  0.007) and shortened overall survival (p  =  0.007). CONCLUSIONS: In accordance with data concerning maspin expression in colorectal cancers, the expression of this protein in the invasive front of primary melanomas seems to correlate with local infiltration and tumor aggressiveness. Strong maspin expression in the invasive margin of primary melanomas therefore might reflect an aggressive tumor phenotype.

Photoaging Mobile Apps as a Novel Opportunity for Melanoma Prevention: Pilot Study.

BACKGROUND: Around 90% of melanomas are caused by ultraviolet (UV) exposure and are therefore eminently preventable. Unhealthy tanning behavior is mostly initiated in early adolescence, often with the belief that it increases attractiveness; the problems related to skin atrophy and malignant melanoma are too far in the future to fathom. Photoaging desktop programs, in which an image is altered to predict future appearance, have been successful in positively influencing behavior in adiposity or tobacco prevention settings. OBJECTIVE: To develop and test a photoaging app designed for melanoma prevention. METHODS: We harnessed the widespread availability of mobile phones and adolescents' interest in appearance to develop a free mobile app called Sunface. This app has the user take a self-portrait (ie, a selfie), and then photoages the image based on Fitzpatrick skin type and individual UV protection behavior. Afterward, the app explains the visual results and aims at increasing self-competence on skin cancer prevention by providing guideline recommendations on sun protection and the ABCDE rule for melanoma self-detection. The underlying aging algorithms are based on publications showing UV-induced skin damage by outdoor as well as indoor tanning. To get a first impression on how well the app would be received in a young target group, we included a total sample of 25 students in our cross-sectional pilot study with a median age of 22 (range 19-25) years of both sexes (11/25, 44% female; 14/25, 56% male) attending the University of Essen in Germany. RESULTS: The majority of enrolled students stated that they would download the app (22/25, 88%), that the intervention had the potential to motivate them to use sun protection (23/25, 92%) and that they thought such an app could change their perceptions that tanning makes you attractive (19/25, 76%). Only a minority of students disagreed or fully disagreed that they would download such an app (2/25, 8%) or that such an app could change their perceptions on tanning and attractiveness (4/25, 16%). CONCLUSIONS: Based on previous studies and the initial study results presented here, it is reasonable to speculate that the app may induce behavioral change in the target population. Further work is required to implement and examine the effectiveness of app-based photoaging interventions within risk groups from various cultural backgrounds.

Highly regioselective synthesis of a 3-O-sulfonated arabino Lewis(a) asparagine building block suitable for glycopeptide synthesis.

Using the stannylene method, the trisaccharide 2-acetamido-3-O-[6-O-benzyl-beta-D-galactopyranosyl]-4-O-[2,3,4-tri-O-benzyl-beta-D-arabinopyranosyl]-6-O-benzyl-2-deoxy-beta-D-glucopyranosyl azide was regioselectively sulfonated and, after reduction of the anomeric azide, coupled to Fmoc alpha-allyl aspartate. After Pd(0)-catalyzed deallylation, the sulfatyl Lewis(a) asparagine building block was obtained, suitable for solid-phase glycopeptide synthesis applying the fluoride labile PTMSEL linker system.