Melanoma-specific survival is worse in the elderly: a multicentric cohort study.

We aimed to characterise cutaneous melanoma in the elderly and determine its association with poorer prognosis. We studied a prospective cohort of the melanoma population in Catalonia between 2012 and 2016. We compared young patient group (<75 years old) with elderly patient group (≥75 years old). We included 3009 patients (52.5% women) from 14 centres, with a mean age at diagnosis of 61.1 years. In the ≥75-year-old group there was a predominance of men (53.9% vs. 45.5%, P  < 0.001), melanoma was more frequently located in the head and neck area (37.7% vs. 15.5%, P  < 0.001) and lentigo maligna melanoma subtype was significantly more frequent (31.4% vs. 11.6%, P  < 0.001), as were nodular melanoma and acral lentiginous melanoma ( P  < 0.001). In older people, Breslow index, the presence of ulceration and mitotic rate were higher than in younger people. Kaplan-Meier survival curves showed longer melanoma-specific survival (MSS) and melanoma-free survival (MFS) in <75-year-old group compared to the elderly group. Cox regression models demonstrated reduced MSS in patients ≥75 years regardless of gender, location, IB, ulceration and lymph node status at diagnosis (HR 1.54, P  = 0.013) whereas MFS was not independently associated with elderly when head and neck location was considered. Age appears to be an independent risk factor for MSS but not for MFS. Worse melanoma prognosis in elderly could be explained by factors unrelated to the tumour, such as age-related frailty and comorbidities that limit the access to systemic treatments and, eventually, age-related immune dysfunction.

Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients" International Study.

BACKGROUND: The introduction of cyclin-dependent kinase inhibitors (CDK4/6i) was a great advance in therapeutics for patients with estrogen receptor+/human epidermal growth factor receptor (HER2) locally advanced and metastatic breast cancer. Despite the increasing use of these agents, their adverse drug-related events have not yet been fully characterized. We describe the spectrum of cutaneous adverse reactions occurring in advanced breast cancer patients treated with cyclin-dependent kinase inhibitors, analyzing types, severity, time to onset, and possible treatment outcomes. METHODS: We performed a multicentric retrospective study including patients with advanced breast cancer who developed cutaneous lesions during treatment with CDK4/6i in the period from June 2020 to June 2021. Patients > 18 years were recruited at eleven onco-dermatology units located in Albania (1), Argentina (1), France (1), Greece (3), Italy (3), and Spain (2). We evaluated patients' epidemiological and clinical characteristics, types of cutaneous adverse events, their time to onset, and treatment outcomes. The severity of the skin reactions was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 score. RESULTS: Seventy-nine patients (median age: 62.3 years; range 39-83 years) were included in the study, and, collectively, we recorded a total of 165 cutaneous adverse events during follow-up visits. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and eczematous lesions (24/79). Cutaneous toxicities were usually mild in severity (>65%) and occurred after a median of 6.5 months. Only four patients (5%) required treatment discontinuation due to the severity of the skin lesions. The majority of the skin reactions were managed with topical treatments. CONCLUSIONS: To the best of our knowledge, we present the largest case series of cutaneous adverse events developing in advanced breast cancer patients treated with CDK4/6i. We showed that cutaneous toxicities are usually mild in severity, and manageable with standard supportive care; however, in selected cases, they can lead to treatment discontinuation with possible implications for patients' clinical outcomes.

Loss of dyskerin facilitates the acquisition of metastatic traits by altering the mevalonate pathway.

The initial dissemination of cancer cells from many primary tumors implies intravasation to lymphatic nodes or blood vessels. To investigate the mechanisms involved, we analyzed the expression of small non-coding RNAs in cutaneous squamous cell carcinoma (cSCC), a prevalent tumor that mainly spreads to lymph nodes. We report the reduced expression of small nucleolar RNAs in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (dyskerin, which stabilizes the small nucleolar RNAs) along the metastasis. DKC1 depletion in cSCC cells triggered lipid metabolism by altering the mevalonate pathway and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial-to-mesenchymal transition. Consistently, the expression of the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 was associated with pathological features of high metastatic risk in cSCC patients. Our data underpin the relevance of the mevalonate metabolism in metastatic dissemination and pave the possible incorporation of therapeutic approaches among the antineoplastic drugs used in routine patient care.

Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.

BACKGROUND: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). OBJECTIVES: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. METHODS: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. RESULTS: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01-0·76] and vitiligo (OR 0·07, 95% CI 0·006-0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02-0·31), lichenoid reactions (OR 0·15, 95% CI 0·03-0·77) and eczematous reactions (OR 0·24, 95% CI 0·07-0·78), all compared with pruritic rash. CONCLUSIONS: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy. Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer. The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus. Clinical awareness and specialized dermatological consultation should be advocated.

Severe blistering eruptions induced by immune checkpoint inhibitors: a multicentre international study of 32 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), bullous life-threatening reactions are rare. To better define the clinical and histological features, treatment, and prognosis of ICI-related severe blistering cutaneous eruptions. This retrospective case series was conducted between 2014/05/15 and 2021/04/15 by the dermatology departments of four international registries involved in drug reactions. Inclusion criteria were age ≥18 years old, skin eruption with blisters with detachment covering ≥1% body surface area and at least one mucous membrane involved, available pictures, and ICI as suspect drug. Autoimmune bullous disorders were excluded. Each participant medical team gave his own diagnosis conclusion: epidermal necrolysis (EN), severe lichenoid dermatosis (LD), or unclassified dermatosis (UD). After a standardized review of pictures, cases were reclassified by four experts in EN or LD/UD. Skin biopsies were blindly reviewed. Thirty-two patients were included. Median time to onset was 52 days (3-420 days). Cases were originally diagnosed as EN in 21 cases and LD/UD in 11 cases. After review by experts, 10/21 EN were reclassified as LD/UD. The following manifestations were more frequent or severe in EN: fever, purpuric macules, blisters, ocular involvement, and maximal detachment. Most patients were treated with topical with or without systemic corticosteroids. Eight patients (25%) died in the acute phase. The culprit ICI was not resumed in 92% of cases. In three patients, another ICI was given with a good tolerance. Histology did not reveal significant differences between groups. Severe blistering cutaneous drug reactions induced by ICI are often overdiagnosed as EN. Consensus for management is pending.

Thermal fluctuation and conformational effects on NMR parameters in ß-O-4 lignin dimers from QM/MM and machine-learning approaches.

Advanced solid-state and liquid-state nuclear magnetic resonance (NMR) approaches have enabled high throughput information about functional groups and types of bonding in a variety of lignin fragments from degradation processes and laboratory synthesis. The use of quantum chemical (QM) methods may provide detailed insight into the relationships between NMR parameters and specific lignin conformations and their dynamics, whereas a rapid prediction of NMR properties could be achieved by combining QM with machine-learning (ML) approaches. In this study, we present the effect of conformations of ß-O-4 linked lignin guaiacyl dimers on 13C and 1H chemical shifts while considering the thermal fluctuations of the guaiacyl dimers in water, ethanol and acetonitrile, as well as their binary 75 wt% aqueous solutions. Molecular dynamics and QM/MM simulations were used to describe the dynamics of guaiacyl dimers. The isotropic shielding of the majority of the carbon nuclei was found to be less sensitive toward a specific conformation than that of the hydrogen nuclei. The largest 1H downfield shifts of 4-6 ppm were established in the hydroxy groups and the rings in the presence of organic solvent components. The Gradient Boosting Regressor model has been trained on 60% of the chemical environments in the dynamics trajectories with the NMR isotropic shielding (σiso), computed with density-functional theory, for lignin atoms. The high efficiency of this machine-learning model in predicting the remaining 40% σiso(13C) and σiso(1H) values was established.

Oral submucous fibrosis presenting with histopathological lichenoid changes as predominant feature: Report of five cases and review of the literature.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity associated with habitual chewing of quid, with a high incidence among populations of the Indian subcontinent and Southeast Asia. Clinically, its initial manifestation may mimic oral lichen planus or lichen sclerosus. If the habit is not halted, the mucosa gets leathery and thickened, and fibrous bands form causing significant morbidity. Microscopically, it is characterized by atrophic epithelium, loss of rete ridges, and hyalinization of lamina propria. Of note, these hallmark histopathological features may be overlooked in the unusual presence of lichenoid interface changes, which may lead to the wrong diagnosis. We present herein five cases in which the rare joint appearance of OSF and lichenoid reaction features posed a diagnostic challenge. Due to its progressive nature and malignant potential, the presence of oral lichenoid changes overlying submucous hyalinization, in the right clinical and demographic setting, should raise suspicion of OSF and prompt actions directed at quid-chewing discontinuation.

Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair.

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhibition prevents activation of the DNA-damage repair (DDR) pathway in colorectal cancer thus potentiating the effect of chemotherapy. We now show that different chemotherapy agents inflict DNA damage in MM cells, which is efficiently repaired, associated with activation of the ATM-dependent DDR machinery. Pharmacologic inhibition of BRAF impairs ATM and DDR activation in these cells, leading to sustained DNA damage. Combination treatments involving DNA-damaging agents and BRAF inhibitors increase tumor cell death in vitro and in vivo, and impede MM regrowth after treatment cessation. We propose to reconsider the use of chemotherapy in combination with BRAF inhibitors for MM treatment.

Diagnostic accuracy of pigmented labial macules by in vivo reflectance confocal microscopy and correlation among techniques.

BACKGROUND: Pigmented labial macules (PLMs) are clinical, dermoscopic, and histopathologic challenges. OBJECTIVE: To describe and evaluate the utility of reflectance confocal microscopy (RCM) in PLMs and to establish a correlation between dermoscopy, RCM, histopathology, and immunohistochemistry. METHODS: Prospective study of PLMs from 4 tertiary referral dermatology centers. The study included 51 biopsy specimen-proven PLMs. Dermoscopic, RCM images, and histopathologic preparations were evaluated for malignant criteria. Diagnostic accuracy of RCM for melanoma diagnosis, RCM Lip Score previously reported, and κ values between techniques were calculated. RESULTS: Included were 5 melanomas and 46 benign PLMs. Dermoscopically, melanomas exhibited more frequently ≥3 colors and ≥3 structures. With RCM, pagetoid spreading, epithelial disarray, continuous proliferation of atypical cells around papillae, nonhomogeneously distributed papillae, marked cellular atypia, and a higher number of dendritic cells per papillae were more frequent in melanomas. The RCM Lip Score was significantly higher in malignant lesions. Good κ values were observed in most of the evaluated features. A perfect sensitivity and specificity was obtained combining dermoscopy and RCM. LIMITATIONS: A low number of melanomas were obtained. CONCLUSIONS: RCM improves lip melanoma diagnosis, and the RCM Lip Score represents a useful tool for the evaluation of a PLM.

Diffuse dermal mucinosis secondary to colony-stimulating factor 1 receptor monoclonal antibody treatment: A novel and peculiar drug-induced diffuse cutaneous mucinosis.

Colony-stimulating factor 1 receptor (CSF1R) inhibitors represent a new class of immune-modulatory drugs, mostly investigated in clinical trials in different malignant neoplasms. Four patients, diagnosed with recurrent or advanced malignant neoplasm and treated with a combination of anti-programmed death ligand 1 and anti-CSF1R monoclonal antibodies, developed an asymptomatic cutaneous eruption characterized by an ill-defined pseudoedematous to waxy diffuse infiltration with a reticular cobblestone-like pattern. Histopathological examination revealed diffuse mucin deposition involving the superficial and mid-dermis with fragmented and scattered elastic fibers. The exact pathogenic mechanisms implicated in the development of mucin deposits in patients treated with CSF1R inhibitors remain to be elucidated. A reduced degradation and clearance of components of the extracellular matrix by macrophages secondary to CSF1 pathway inhibition may be hypothesized. Shredding and fragmentation of elastic fibers may be a result of the increased accumulation of mucopolysaccharides. This observation illustrates the new spectrum of skin-related toxicities secondary to new targeting therapies. This may contribute to a better understanding of the underlying pathogenic mechanisms in skin diseases characterized by a persistent dermal glycosaminoglycan deposition.

Academic Performance of Immigrant Students and Teachers' Expectations / Desempenho Acadêmico de Alunos Imigrantes e Expectativas Docentes / Rendimiento Académico de los Estudiantes Inmigrantes y Expectativas Docentes

Abstract This study focuses on whether teachers' thinking is prophetic, that is, whether these attitudes and actions permeate the students and condition their academic performance. To this end, we analyzed the beliefs of 167 teachers of Early Childhood, Elementary and High School Education in the province of Córdoba (Spain). A questionnaire was used to know the relationship between teachers' beliefs about immigrant students and their possible influence on academic achievements. In the first place, the findings show the teachers' lack of confidence in non-native students, a phenomenon that is largely unconscious; in the second place, lower school results in these students in relation to natives; and, finally, an external attributional style in teachers, for whom the families and the organizational resources of the school institution, not them, are the determining factors of school achievement.

Resumo Este estudo teve por objetivo investigar se o pensamento dos professores é um pensamento profético, ou seja, se suas atitudes e ações sugestionam os alunos e condicionam o seu desempenho acadêmico. Para este fim, são analisadas as crenças de 167 professores de Educação Infantil, Educação Básica e Ensino Médio da província de Córdoba (Espanha). Foi utilizado um questionário para saber a relação entre os alunos imigrantes e sua possível influência no desempenho acadêmico. Os resultados mostram, em primeiro lugar, a baixa confiança dos professores nos alunos não nativos, fenômeno em grande parte inconsciente; em segundo lugar, registra-se um desempenho acadêmico mais baixo neste corpo discente em relação aos autóctones e, finalmente, um estilo de atribuição externo aos professores, para os quais as famílias e os recursos organizacionais da instituição escolar, e não eles, são os fatores determinantes do desempenho acadêmico.

Resumen El presente estudio de investigación se centra en conocer si el pensamiento del docente es un pensamiento profético, es decir, si esas actitudes y acciones docentes penetran en el alumnado y condicionan su desempeño académico. Para ello se analizan las creencias de 167 docentes de Educación Infantil, Educación Primaria y Educación Secundaria de la provincia de Córdoba (España). Se utilizó un cuestionario para conocer la relación entre el alumnado inmigrante y su posible influjo en el logro académico. Los hallazgos evidencian, en primer lugar, la escasa confianza del profesorado en el alumnado no autóctono, fenómeno que es en gran medida inconsciente; en segundo lugar, resultados escolares más bajos en este alumnado con relación al autóctono; y, finalmente, un estilo atribucional externo en los docentes, para quienes las familias y los recursos organizativos de la institución escolar, no ellos, son los factores determinantes del logro escolar.

Molecular Insight into the Cosolvent Effect on Lignin-Cellulose Adhesion.

Understanding and controlling the physical adsorption of lignin compounds on cellulose pulp are key parameters in the successful optimization of organosolv processes. The effect of binary organic-aqueous solvents on the coordination of lignin to cellulose was studied with molecular dynamics simulations, considering ethanol and acetonitrile to be organic cosolvents in aqueous solutions in comparison to their monocomponent counterparts. The structures of the solvation shells around cellulose and lignin and the energetics of lignin-cellulose adhesion indicate a more effective disruption of lignin-cellulose binding by binary solvents. The synergic effect between solvent components is explained by their preferential interactions with lignin-cellulose complexes. In the presence of pure water, long-lasting H-bonds in the lignin-cellulose complex are observed, promoted by the nonfavorable interactions of lignin with water. Ethanol and acetonitrile compete with water and lignin for cellulose oxygen binding sites, causing a nonlinear decrease in the lignin-cellulose interactions with the amount of the organic component. This effect is modulated by the water exclusion from the cellulose solvation shell by the organic solvent component. The amount and rate of water exclusion depend on the type of organic cosolvent and its concentration.

Incidence of Melanoma in Catalonia, Spain, Is Rapidly Increasing in the Elderly Population. A Multicentric Cohort Study.

The incidence of melanoma has been increasing worldwide during recent decades. The objective of the study was to analyse the trends in incidence for in situ and invasive melanoma in the Spanish region of Catalonia during the period of 2008-2017. We designed a cross-sectional study with an age-period-cohort analysis of melanoma patient data from the Network of Melanoma Centres in Catalonia. Our database covered a population of over seven million and included a total of 8626 patients with incident melanoma. The main outcome measures were crude and age-standardised incidence rates to the European 2013 standard population. Joinpoint regression models were used to evaluate the population trends. We observed an increase in the age-standardised incidence rate (per 100,000 population) of all melanoma subtypes from 11.56 in 2008 to 13.78 in 2017 with an average annual percent change (AAPC) of 3.5%. This incidence increase was seen exclusively in the older population. Moreover, the stratified analysis showed a statistically significant increase in the age-standardised incidence rate for invasive (AAPC 2.1%) and in situ melanoma (AAPC 6.5%). In conclusion, the incidence of melanoma has continued to increase in the elderly population over recent decades, with a rapidly increasing trend of in situ melanomas and the lentigo maligna subtype.

Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel.

Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood. In this study, we evaluated the gene expression profiles of actinic keratosis lesions before and after treatment with ingenol mebutate using microarray technology. Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evaluated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 consecutive days. Diagnostic and clearance of lesions was determined by clinical, dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Differentially expressed genes were identified, and enrichment analyses were performed using STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebutate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially expressed genes were identified following treatment, and downregulated genes (114 of 128) revealed changes in pathways important to epidermal development, keratinocyte differentiation and cornification. In responder patients, 388 downregulated genes (of 450 differentially expressed genes) were also involved in development/differentiation of the epidermis, and immune system-related pathways, such as cytokine and interleukin signaling. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, differentially expressed genes were mainly associated with cornification, keratinization and keratinocyte differentiation. Overall, the present study provides insight into the gene expression profile of actinic keratoses after treatment with ingenol mebutate, as well as identification of genetic signatures that could predict treatment response.