Dupilumab, blocking IL-4 and IL-13 signals, improves atopic dermatitis and Quality of Life but might be also associated with the occurrence of ocular adverse events (OAEs). The main objective of our ...prospective study was to characterize the cytokine and chemokine profile in the tear fluid of dupilumab-treated patients with moderate-to- severe atopic dermatitis and to identify biomarkers predicting the occurrence of ocular adverse events. Patients with moderate-to-severe AD underwent dermatological and ophthalmological evaluation at the baseline (T0) and week 16 or at the time of an eventual ocular adverse events (T1). A multiplex immunoassay measuring multiple cytokines and chemokines in the tear fluid extracted during ocular examination at both T0 and T1 was performed. Thirty-nine patients with moderate-to-severe AD and treated with dupilumab were included in the study. Baseline tear fluid levels revealed a significantly higher concentration of type 2 cytokines and chemokines in AD patients than healthy controls. The occurrence of ocular adverse events during dupilumab therapy was associated with a significant increase of IL-33 tear fluid levels and a significantly lower tear break-up time, this latter also identified as predictive factor. Our findings suggest that the ophthalmological examination should be considered a valid support to identify patients at risk of developing OAEs and to provide their appropriate management.
Cutaneous squamous cell carcinoma (cSCC) represents 20% of all skin cancers. Although primary cSCCs can be successfully treated with surgery, a subset of highly aggressive lesions may progress to ...advanced disease, representing a public healthcare problem with significant cancer‐related morbidity and mortality. A complex network of genes (TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) have been shown to play an important role in the pathogenesis of cSCC. The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH‐activating agents capable to restore its tumour‐suppressor function. EGFR inhibitors including both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors (erlotinib, gefitinib and dasatinib) have been used in clinical trials for the treatment of advanced cSCC, achieving only partial clinical benefit. Recently, an immune‐modulatory drug (cemiplimab) has been introduced for the treatment of advanced cSCC with good clinical results and a favourable safety profile, while other PD1/PD‐L1 inhibitors, either as monotherapy or in combination with targeted therapies, are currently under investigation. This review focuses on molecular findings involved in the pathogenesis of cSCC and their implications for the future development of new treatment strategies. In addition, current and ongoing treatments on targeted therapies and/or immunotherapy are illustrated.
Background
Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, ...characterized by high UV exposure and dark‐skinned individuals, are underrepresented.
Objectives
We report a comprehensive pooled analysis of established high‐ and intermediate‐penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium.
Methods
Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country.
Results
We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3–19.7), >3 affected members (OR 2.6; 95% CI 1.3–5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4–9.4) in the family (AUC 0.76, 95% CI 0.71–0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0–2.0 and OR 4.3; 95% CI 1.2–14.6, respectively).
Conclusions
Variants in known high‐penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.
Mutations in MAPK signalling genes are driver events in melanoma, and have therapeutic relevance in the metastatic and adjuvant setting. This study evaluated the intra-patient heterogeneity of BRAF, ...NRAS and c-KIT mutational status between 30 primary melanomas and 39 related metastases, using molecular analysis and immunohistochemistry. BRAF mutations were identified in 46.7% of primary melanomas and 48.7% of metastases and NRAS mutations in 20% and 25.6%, respectively. Intra-patient heterogeneity was detected in 13.3% of patients for both BRAF and NRAS genes and was not associated with clinico-pathological characteristics of melanomas or metastases. High consistency was observed between immunostaining and molecular methods for BRAFV600E (k = 0.90; p < 0.001) and NRASQ61R (k = 0.87; p < 0.001). These findings demonstrate a relevant intra-patient heterogeneity between primary and metastatic lesions that is independent of clinical variables and methodological approach.
Tralokinumab is a human monoclonal antibody targeting interleukin-13 that is approved for the treatment of moderate-severe atopic dermatitis. Studies analyzing the efficacy and safety of tralokinumab ...in a real-world setting are scarce.
A European, multicentric, real-world, retrospective cohort study was defined to assess the effectiveness and safeness profile of tralokinumab, investigating the achievement of pre-specified treatment goals; and to detect potential differences in terms of effectiveness and safeness across some selected patient subcohorts.
A total of 194 adult patients were included in this study. A significant improvement in physician-assessed disease severity was detected at each follow-up visit as compared with baseline and similar trend was observed for patient-reported outcomes and quality of life. No meaningful difference in effectiveness was found when considering patient age (<65 versus ≥65 years), neither dissecting patient cohort in dupilumab-naive vs dupilumab-treated subjects. Among tralokinumab-treated patients, 88% achieved at least one currently identified real-world therapeutic goal at week 16.
This retrospective multicenter study confirmed the effectiveness and safeness of tralokinumab throughout 32 weeks of observation, showing the achievement of therapeutic goals identified in both trial and real-world settings in a large proportion of tralokinumab-treated patients.
Background
A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients.
...Objective
We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents.
Methods
One‐hundred‐twenty‐three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico‐pathological characteristics was evaluated.
Results
Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi.
Conclusion
Our results confirm the scarce involvement of the major high‐risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.
Linked Commentary: H. Helgadottir. J Eur Acad Dermatol Venereol 2022; 36: 167–168. https://doi.org/10.1111/jdv.17879.
The Biotin-Streptavidin complex is a widely studied system in biology and biophysics, because of its extremely strong non-covalent binding affinity. The latter is often exploited to link molecules to ...substrates or to one another. However, the details of the Biotin-Streptavidin binding have not been fully elucidated so far. Particularly, the role of cooperative effects in enhancing the binding affinity has not been clarified. Our long-term aim is to investigate this point by implementing two complementary approaches, fluorescence correlation spectroscopy and time-correlated single-photon counting. As both methods rely on the analysis of fluorescence signals, biotin labeled with Atto-550-dye was used. In this work, in order to get a first overview of the system, we analyzed solutions in three paradigmatic ranges of Biotin-to-Streptavidin concentration ratio. Fluorescence correlation spectroscopy measurements allowed us to extract diffusion times of free biotin and of biotin-Streptavidin complexes, and also to gain information about the dynamics of the intersystem crossing between the first excited triplet and the first excited singlet states. Time-correlated single-photon counting made it possible to derive the lifetimes of the different species in solution, as well as to deduce relevant information about the relative abundance of Streptavidin-complexed and free Biotin.
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