Effective Anti-SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders.

BACKGROUND: Mast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published. OBJECTIVE: To study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting. METHODS: Clinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti-SARS-CoV-2-specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies. RESULTS: Overall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2-specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2-specific, IFN-γ-producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden). CONCLUSIONS: Patients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.

Acute kidney injury in patients treated with anti-programmed death receptor-1 for advanced melanoma: a real-life study in a single-centre cohort.

BACKGROUND: Immune checkpoints inhibitors have transformed the prognosis of advanced melanoma but are associated with immune-related adverse events (irAEs). We evaluated the incidence, risk factors and causes of acute kidney injury (AKI) in a monocentric real-life cohort of patients treated with anti-programmed death receptor-1 (anti-PD1) antibodies for advanced melanoma. METHODS: Retrospective collection of medical charts and comprehensive analysis of lab results from patients treated with nivolumab or pembrolizumab for advanced melanoma between 2014 and 2018 was carried out. AKI was defined by Kidney Disease Improving Global Outcomes criteria, and causes were determined by chart review. Overall survival, survival without AKI and impact of AKI on survival were analysed. Risk factors for death and for AKI were identified. RESULTS: Two hundred and thirty-nine patients were included. Forty-one (17%) had at least one episode of AKI. Independent risk factors for AKI were treatment with renin-angiotensin-aldosterone system inhibitors (RAASi), pre-existing chronic kidney disease (CKD) and cumulated doses of anti-PD1. The main cause of AKI was prerenal, and only eight patients (3.3%) developed acute interstitial nephritis; 8% of patients developed CKD. The median overall survival was 13.4 months and was not affected by AKI. In multivariate analysis, the overall mortality was lower in overweight and obese patients and higher in patients treated with proton-pump inhibitors (PPI) or corticosteroids. CONCLUSIONS: AKI is common in patients treated with anti-PD1 for advanced melanoma but is mostly prerenal and favoured by the use of RAASi; renal irAE is rare. PPI and corticosteroids were associated with poor survival in this population, while overweight/obesity was protective.

BIABooster: Online DNA Concentration and Size Profiling with a Limit of Detection of 10 fg/µL and Application to High-Sensitivity Characterization of Circulating Cell-Free DNA.

We describe a technology to perform sizing and concentration analysis of double stranded DNA with a sensitivity of 10 fg/µL in an operating time of 20 min. The technology is operated automatically on a commercial capillary electrophoresis instrument using electro-hydrodynamic actuation. It relies on a new capillary device that achieves online concentration of DNA at the junction between two capillaries of different diameters, thanks to viscoelastic lift forces. Using a set of DNA ladders in the range of 100-1500 bp, we report a sizing accuracy and precision better than 3% and a concentration quantification precision of ∼20%. When the technology is applied to the analysis of clinical samples of circulating cell-free DNA (cfDNA), the measured cfDNA concentrations are in good correlation with those measured by digital PCR. Furthermore, the cfDNA size profiles indicate that the fraction of low molecular weight cfDNA in the range of 75-240 bp is a candidate biomarker to discriminate between healthy subjects and cancer patients. We conclude that our technology is efficient in analyzing highly diluted DNA samples and suggest that it will be helpful in translational and clinical research involving cfDNA.

New insights into naevoid melanomas: a clinicopathological reassessment.

AIMS: Because the term 'naevoid melanoma' has variable clinical and pathological interpretations, we aimed to clarify the features of melanomas referred to as naevoid. METHODS AND RESULTS: A review was undertaken of 102 melanomas diagnosed histopathologically as naevoid melanomas and ascertained by European Organization for Research and Treatment of Cancer Melanoma Group Subcommittee pathologists from their records. We found these could be classified morphologically into three groups. Thirteen melanomas were overlying genuine naevi and were therefore excluded. Of the 89 melanomas considered to be naevoid, 11 presented clinically as exophytic papillomatous nodules with little junctional component and composed of small atypical cells showing numerous mitoses and no change with depth; we termed these 'papillomatous naevoid' melanomas. The other 78 were flat or only slightly raised, and had a superficial spreading melanoma-like component with maturation to a small cell, but still an atypical, dermal component; we termed these 'maturing naevoid' melanomas. We showed that papillomatous and maturing naevoid melanomas also have differing immunochemical profiles. Preliminary clinical follow-up suggested different outcomes for these two naevoid melanoma types. CONCLUSIONS: Melanomas that have been classified as naevoid melanomas comprise two types with distinct clinical, histopathological and immunohistochemical features that may also be prognostically significant.

Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma.

OBJECTIVE: Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up. DESIGN AND PATIENTS: Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille. METHODS: Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded. RESULTS: Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (≥11.5%) at 9.5±5.9 weeks (mean±s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients. CONCLUSION: Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.

(123)I-BZA2 as a melanin-targeted radiotracer for the identification of melanoma metastases: results and perspectives of a multicenter phase III clinical trial.

UNLABELLED: Our group has developed a new radiopharmaceutical, (123)I - N-(2-diethylaminoethyl)-2-iodobenzamide ((123)I-BZA2), a benzamide derivative able to bind to melanin pigment in melanoma cells. In a prospective and multicentric phase III clinical study, the value of (18)F-FDG PET/CT and (123)I-BZA2 scintigraphy was compared for melanoma staging. METHODS: Patients with a past history of cutaneous or ocular melanoma were included from 8 hospitals. (18)F-FDG imaging was performed according to a standard PET protocol. Whole-body, static planar, and SPECT/CT (if available) images were acquired 4 h after injection of a 2 MBq/kg dose of (123)I-BZA2. (18)F-FDG and (123)I-BZA2 sensitivity and specificity for the diagnosis of melanoma metastasis were calculated and compared on both a lesion basis and a patient basis. True-positive and true-negative lesion status was determined after 6 mo of clinical follow-up or according to lesion biopsies (if available). Melanin content in biopsies was evaluated with the standard Fontana-Masson silver method and was correlated with (123)I-BZA2 uptake. Based on statistical analysis, the number of inclusions was estimated at 186. RESULTS: In all, 87 patients were enrolled from 2008 to 2010. Of these, 45 (52%) had metastases. A total of 338 imaging abnormalities were analyzed; 86 lesions were considered metastases, and 20 of 25 lesion biopsies found melanoma metastases. In a patient-based analysis, the sensitivity of (18)F-FDG for diagnosis of melanoma metastases was higher than that of (123)I-BZA2, at 87% and 39%, respectively (P < 0.05). For specificity, (18)F-FDG and (123)I-BZA2 were not statistically different, at 78% and 94%, respectively. In a lesion-based analysis, the sensitivity of (18)F-FDG was statistically higher than that of (123)I-BZA2 (80% vs. 23%, P < 0.05). The specificity of (18)F-FDG was lower than that of (123)I-BZA2 (54% vs. 86%, P < 0.05). According to biopsy analysis, only 9 of 20 metastatic lesions (45%) were pigmented with high melanin content. (123)I-BZA2 imaging was positive for 6 of 8 melanin-positive lesions, fairly positive for 3 of 10 melanin-negative lesions, and negative for 7 of 10 melanin-negative lesions. The sensitivity and specificity of (123)I-BZA2 for the diagnosis of melanin-positive lesions were 75% and 70%, respectively. Because of a low (123)I-BZA2 sensitivity, this clinical trial was prematurely closed after 87 patients had been included. CONCLUSION: This study confirms the value of (18)F-FDG PET/CT for melanoma staging and strengthens the high accuracy of (123)I-BZA2 for diagnosis of melanin-positive metastatic melanoma. Moreover, benzamide derivatives radiolabeled with therapeutic radionuclide may offer a new strategy for the treatment of metastatic melanoma patients harboring melanin-positive metastases.

[Early detection of melanoma. Discussing a new approach]. / Dépistage du mélanome. Réflexions pour une approche différente.

Mortality by melanoma has not decreased, despite intensive medical screening, multiple campaigns based on ABCD, and a more efficacious surveillance of people at risk by dermatologists. We thus have to modify our strategy and to target the general population. Indeed, most melanomas do not develop in people identified as at risk, 2/3 of melanomas are self-detected by individuals, and melanoma responsible for mortality are often fast-growing ones, which give few opportunities to be detected early enough by chance by a doctor, although they can be by any aware individuals. Public campaigns can make everybody able to self-detection of melanoma, on condition that images of nevi and melanoma are used as educational support, and not artificial algorithms such as ABCD which lead to an overload medical system with irrelevant consultations. Self-surveillance and detection of nevus changes must be promoted by providing all at risk people with photographic references. By training general population and involving its responsibility, anybody who will feel that he has a suspicious lesion should have a direct access to the "diagnostic test", which is the dermatologist opinion, ie the "mammography" of the skin cancer. GPs and occupational doctors by the multiple opportunities to see people skin should go on their major role to detect lesions, which would not be self-detected.

Skin protection by sunscreens is improved by explicit labeling and providing free sunscreen.

Whatever the improvement in the protection spectrum of sunscreens (SCs), actual skin protection mainly depends on the way they are used, especially on the quantity applied. This prospective randomized study assessed how much sun protection factor (SPF) labeling, which is hardly understandable by a layman, and high cost account for misuse of SCs. In three beach resorts in France, 364 individuals were blindly randomized during their holidays to three arms (1) free SCs intervention (FS) = four types of SCs with their usual SPF label (60B-A, 20B-A, 12B-A, 6B-3A) at free disposal; (2) same free SCs with an explicit labeling (FNL), including sunburn protection, likely protection against long-term effects of UV, and possibility to get a tan; and (3) no intervention (NI). As compared to FS, FNL increased the quantity of SCs applied, mainly in the minority of people who were not "tan-seekers", reduced sunburns particularly in sun-sensitive individuals (25.6 vs 58.3%, P=0.005), and induced a shift in the level of SCs chosen. Free delivery SCs were associated with a more systematic application of SCs in case of exposure, and a decreased sunburn occurrence, without increase of exposure. These results suggest that a labeling more explicit for the public would result in a better protection in SC users and that cost could be a limiting factor to use SC as often as necessary.

Superiority of a cognitive education with photographs over ABCD criteria in the education of the general population to the early detection of melanoma: a randomized study.

Most education campaigns for melanoma (MM) detection in the general population have used the "ABCD" algorithm, although recognition of objects in the real life is based on a holistic image recognition rather than on analytic criteria. The objective was to compare analytic (ABCD) and cognitive (photographs) strategies for teaching self-recognition of MM. A prospective 4-arm stratified randomized trial in 255 individuals compared 3 realistic educative interventions by leaflets: 1) ABCD algorithm ("ABCD"), 2) a set of photographs chosen to stimulate recognition of MM among benign pigmented lesions ("Cog"), 3) photographs + explanations ("Cog-Ex" arm) and 4) no intervention ("NI"). A 40-slides test was performed before intervention (T0), 1 week after (T1) and after induction of anxiety (T2). In the "ABCD" arm, sensitivity slightly improved (80 to 83.8%, p = 0.04), but specificity dropped from 65.1 to 56.3% (p < 0.001), with no benefit in accuracy as compared to "NI". In "Cog" arm, there was no change in sensitivity, but a strong increase in specificity (65.9 to 81.1%, p < 0.001) and accuracy (42.1 to 53.1%, p < 0.001). "Cog-ex" resulted in similar although lower benefit. Under stress (T2), there was a dramatic loss of specificity and accuracy in "ABCD" arm (65.1 to 44.1%, p < 0.001 and 40.8% to 35.8%, p < or = 0.001) without higher gain in sensitivity, while sensitivity and accuracy increased (p < 0.005) after "Cog" leaflet, without decreasing specificity. Finally, the "ABCD" message alone does not seem efficacious and is even worse in the context of anxiety, whereas a quick look at a few photographs is sufficient to improve the ability of the laymen to recognize a MM just by optimizing their spontaneous image recognition capacities. Education by photographs is a realistic strategy which should replace or complete "ABCD" message in the campaigns for self-detection of MM.