The ugly duckling describes a nevus that is obviously different from the others in a given individual.¹ This term is used in intrapatient comparative analysis (IPCA) of nevi and is widely recognized as a major indicator for suspicion of melanoma both visually and dermoscopically.^2,3 We previously demonstrated that the ability of a dermatologist to intuitively perceive a nevus that looks different from others relies on the limited diversity of nevi, which constitutes an individual reference system in each patient.⁴ A major benefit for training physicians and facilitating self-detection in the at-risk population may come from understanding the robustness, reliability, and diagnostic effect of the IPCA process using the ugly duckling sign in detection of melanoma. Intrapatient comparative analysis has probably always been unconsciously used by dermatologists to support or modulate the interpretation they make from the morphologic analysis of a given lesion. Two cognitive processes are probably at work: a lesion-focused analysis (LFA) to determine if pigmented lesions are morphologically suspicious nevi (MSN) and identifying a nevus with the ugly duckling sign.⁵ Since LFA and IPCA processes are intrinsically and unconsciously mixed in the physicians’ decision, their respective contribution is not measurable in real-world practice. To estimate the contribution of IPCA to the diagnosis of melanoma, an experimental study with an artificial separation of LFA and IPCA was designed.

Both Gamma-Knife radiosurgery (GKRS) and BRAF inhibitors (BRAF-I) have been shown to be useful in melanoma patients with brain metastases (BMs), thus suggesting that it could be interesting to combine their respective advantages. However, cases of radiosensitization following conventional radiation therapy in BRAF-I treated patients have raised serious concerns about the real feasibility and risk/benefit ratio of this combination. Review by two independent observers of brain magnetic resonance imaging (MRI) follow-up pictures, and volume and edema quantifications, and survival assessment in all patients who had been treated by GKRS and BRAF-I at a single institution. Among 53 GKRS carried out in 30 patients who ever received BRAF-I and GKRS, 33 GKRS were carried out in 24 patients while under BRAF-I treatment, from which only 4 with an interruption of BRAF-I. The 20 other GKRS were carried out in 15 patients (including 9 of the 24) before initiation of BRAF-I treatment. No case of radiation-induced necrosis and no scalp radiation dermatitis occurred. A >20% increase in volume was observed in 35 of the 263 BM treated by GKRS (13.3%), but only 3 clear-cut edemas and 3 hemorrhages were detected within 2 months after GKRS, and 4 edemas and 7 hemorrhages later. Neither the MRI features nor the incidence of the volume changes, hemorrhage and edema were deemed unexpected for melanoma BM treated by GKRS. Median survival from first GKRS under BRAF-I and first dose of BRAF-I were 24.8 and 48.8 weeks, respectively. This series does not show immediate radiotoxicity nor radiation recall, in melanoma patients with BRAF-I whose BMs are treated by GKRS. Interrupting BRAF-I for stereotactic radiosurgery (SRS) of BM seems useless, although it is still advised for other radiation therapies. The potential benefit of combining SRS and BRAF-I can be safely tested.

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Acute type 1 diabetes (AD1) is a rare but definitive immune-related adverse event associated with anti-PD1. Most of the reported cases are close to what has been described as “fulminant type 1 diabetes.” We sought to determine whether anti-PD1 could impair glycoregulation and whether occurrence of AD1 could be anticipated by prior glycemic changes. Fasting glycemia collected before, under, and after treatment in melanoma patients treated with anti-PD1 over a period of 36 months were retrospectively analyzed. Glycemic trend analyses were performed using linear regression analysis. In total, 1470 glucose values were monitored in 163 patients treated for a mean duration of 5.96 months. Three patients developed an AD1 (1, 84%). Two other cases were observed in the same period in a still-blinded trial of anti-PD1 versus ipilimumab. All cases of AD1 occurred in patients with a normal pretreatment glycemia, and there was no detectable drift of glycemia before ketoacidosis onset. In 4 of 5 cases of AD1, the HLA subgroups were DRB01* 03 or 04, known to increase type 1 diabetes risk in the general population. In the 28 patients with preexisting type 2 diabetes, there was a slight trend for glycemia increase with anti-PD1 infusions (0.05 mmol/L/infusion P=0.004). In the 132 patients with normal pretreatment glycemia, there was a slight trend for a decrease of glycemia with anti-PD1 infusions (−0.012/mmol/L/infusion P=0.026). These data suggest that the monitoring of glycemia under anti-PD1 cannot help to anticipate AD1, and there is no general tendency to glycemic disorder. HLA genotyping before treatment may help to focus surveillance in patients with the HLA DRB1*03/04 group.