Real-world study on the use of pegylated interferon alpha-2a for treatment of mycosis fungoides/Sézary syndrome using Time to Next Treatment as a measure of clinical benefit: An EORTC CLTG study.

INTRODUCTION: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon alpha (IFN-α, subtypes 2a and 2b) has been used for MF/SS since 1984, however its production was recently stopped and so the recombinant pegylated (PEG) form of IFN α-2a remains as single IFN alternative treatment, even though not approved for MF/SS. OBJECTIVE: To assess effectiveness and safety of PEG IFN α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in real world setting. METHODS: We conducted an international and multicenter retrospective study of patients with MF and SS at any stage, treated with PEG IFN α-2a, from July 2012 to February 2022. Patients were included across 11 centers in 10 countries. Primary endpoints were to determine TTNT of PEG IFN α-2a and the adverse events (AE) in MF/SS. RESULTS: In total 105 patients were included, mean age was 61 (22-86 years); 42 (40%) with disease stage IA-IIA, 63 (60%) with stage IIB-IVB. PEG IFN α-2a was combined with other therapies in 67 (64%) patients, usually with extracorporeal photopheresis (36%) and bexarotene (22%). Fifty-seven percent of stage I-IIA patients achieved ORR, whereas 51% of stage IIB-IVB. Combination therapy showed a TTNT of 10.4 months, while 7 months in monotherapy (p=0.0099). Overall, TTNT was 9.2 months, ORR was 53% (56/105), CR and PR were 13% and 40%, respectively.AE were described in 69% (72) of the patients. Flu-like symptoms (27%), lymphopenia (23%) and elevated liver function (10%) were the most frequently reported. Grade 3-4 adverse events were reported in 23 (21%) patients, which were mostly related to myelosuppression. LIMITATIONS: retrospective data analysis and unrestricted number of combination therapies. CONCLUSIONS: PEG IFN α-2a for MF/SS showed ORR of 53%, TTNT of 9.2 months, superiority of combination regimens in comparison to monotherapy and doses of 180 mcg/weekly related to higher ORR.

Escabiose: aspectos gerais e a importância no reconhecimento e tratamento precoces / Scabies: general aspects and the importance of early recognition and treatment

A escabiose é uma dermatose infecto parasitária mais prevalente no mundo, sobretudo nas regiões tropicais e em países de baixa renda. Surtos são comuns em locais de aglomeração como presídios, escolas e campos de refugiados, e tanto o atraso no diagnóstico como o tratamento inadequado são responsáveis pela propagação da doença. Este trabalho tem por objetivos destacar os principais aspectos da escabiose bem como as apresentações dermatológicas, a fim de auxiliar no diagnóstico e tratamentos precoces, tendo como foco o médico generalista. O estudo foi realizado no Departamento de Clínica de Dermatologia do Hospital das Clínicas da Faculdade de Medicina de São Paulo (HCFMUSP), através de uma revisão de literatura com acesso aos bancos de dados eletrônicos PubMed. A escabiose é causada pelo Sarcoptes scabiei, caracterizada pelo prurido intenso e por lesões cutâneas sugestivas e localizações típicas, mas que podem variar de acordo com a faixa etária ou estados de imunossupressão. É considerada pela Organização Mundial da Saúde uma doença tropical negligenciada, podendo causar grande impacto socioeconômico e, ainda que com menor frequência, levar a complicações, muitas vezes decorrentes de infecções bacterianas secundárias, sobretudo nas formas mais graves da doença (vistas principalmente em pacientes imunossuprimidos). Por esses motivos, o reconhecimento das principais formas de apresentação clínica e sintomas associados são importantes para que o diagnóstico seja estabelecido de forma breve, possibilitando a instituição correta do tratamento e, com isso, cessando o ciclo de transmissão do ácaro.

Identifying unmet needs and challenges in the definition of a plaque in mycosis fungoides: An EORTC-CLTG/ISCL survey.

BACKGROUND: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking. OBJECTIVES: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate. METHODS: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment. RESULTS: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition. CONCLUSIONS: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters.

A phase 2 study of first-line nivolumab in patients with locally advanced or metastatic cutaneous squamous-cell carcinoma.

BACKGROUND: Cutaneous squamous-cell carcinoma (CSCC) is among the most frequent malignancies worldwide. For those not amenable to treatment with curative intent, immune checkpoint inhibition (ICI) with anti-programmed death receptor 1 (PD-1) antibodies has emerged as a novel therapeutic option. In this study, the authors sought to investigate the activity of the anti-PD-1 agent nivolumab in patients with advanced CSCC (aCSCC). METHODS: CA209-9JC was an open-label, single-arm, phase 2 study to evaluate the safety and/or efficacy of nivolumab in systemic treatment-naive patients with aCSCC. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or 12 months of treatment. The primary end point was the best objective response rate (BORR) as per RECIST 1.1 criteria. Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-four patients with aCSCC were enrolled with a median age of 74 years (range, 48-93). Among the 24 patients evaluable for response, the BORR was 58.3% (14/24); there were no complete responses. With a median follow-up of 17.6 months, median duration of response has not been reached, and the estimated median PFS and OS were 12.7 and 20.7 months, respectively. Prior exposure to radiotherapy was associated with worse outcomes (p = .035, univariate analysis). Treatment-related adverse events of any grade and grade ≥ 3 occurred in 21 (87.5%) and six (25%) patients, respectively, and one patient discontinued nivolumab due to toxicities. CONCLUSIONS: Nivolumab resulted in robust antitumor activity, sustained responses, and good tolerability in systemic treatment-naive patients with aCSCC. These data provide further evidence to support the use of ICI as the standard treatment of aCSCC.

Ensino de mandos para pessoas com tea: uma revisão sistemática / Mand Teaching for People with asd: A Systematic Review / Enseñanza de mandos para personas con tea: una revisión sistemática

O ensino de mando para pessoas com Transtorno do Espectro Autista (tea) tem sido tema frequente de in-vestigações analítico-comportamentais. Algumas revi-sões conceituais e sistemáticas sobre o ensino de mando foram realizadas, mas elas apresentam limitações que o presente estudo buscou superar. A presente revisão sis-temática analisou estudos experimentais sobre o ensino de mandos para pessoas com tea buscando identificar: (a) características dos participantes, ambientes experi-mentais, variáveis independente (vi) e dependente (vd), e resultados obtidos; e (b) investigar possíveis relações entre as categorias analisadas. Uma busca nas bases de dados scopus, Web of Science e pubmed utilizando o termo "mand*", combinado com os termos "autism", "developmental disabilit*" ou "intellectual disabilit*", resultou, após a aplicação dos critérios de inclusão/ex-clusão, na identificação de 176 artigos publicados até setembro de 2020. A maioria dos estudos foi realizada em escolas, com crianças com repertório verbal pré-existente. As vis e vds mais comuns foram reforçamento diferen-cial e fornecimento de ajuda e manipulação da operação motivadora para o ensino de mando por item/informação, e treino de comunicação funcional para redução de com-portamentos-problema. A maioria dos procedimentos de ensino mostrouse pelo menos parcialmente eficaz para todas as vds avaliadas, sendo importante a realização de análises mais detalhadas da variação desses resultados com relação aos repertórios pré-intervenções dos parti-cipantes. Sugere-se a necessidade de mais investigações com pessoas com comportamento verbal ausente ou limitado, e em jovens e adultos com tea.

Mand training for people with autism spectrum disorder (asd) has been frequent in behavioral-analytic inves-tigations. Some conceptual and systematic reviews on mand teaching have been carried out, but they have limitations the present study sought to overcome. The present systematic review analyzed experimental stu-dies in mand teaching for people with asd, seeking to identify (a) participants' characteristics, settings, independent (iv) and dependent variables (dv), and results, and (b) to explore possible relations across the analyzed categories. Searches in the databases Scopus, Web of Science, and PubMed using the term "mand*" combined with the terms "autism," "developmental disability"*, or "intellectual disability*" found, after applying the inclusion/exclusion criteria, 176 articles published up to September 2020. Most studies were conducted in schools with children with a pre-existing verbal repertoire. The most used ivs and DVs were di-fferential reinforcement, prompts, and establishment of motivating operations to teach mands for items/information, and functional communication training to problem behavior reduction. There was at least partial effectiveness in most of the teaching interventions of all dvs identified; however, it seems important to pro-vide more detailed analyses of how these outcomes vary with the participants ́ pre-intervention repertoires. Further investigations of mand training for people with absent or limited verbal repertoire and young people and adults with asd are suggested.

La enseñanza de mando para personas con Trastorno del Espectro Autista (tea) ha sido un tema frecuente de investigaciones desde el análisis de comportamiento. Se realizaron algunas revisiones conceptuales y sistemáticas sobre la enseñanza de mando, pero estas presentan limitaciones que el presente estudio buscó superar. Esta revisión sistemática analizó estudios experimentales sobre la enseñanza de mandos para personas con tea, buscando identificar: (a) características de los participantes, ambientes experimentales, variables independientes (vi) y dependientes (vd) y los resultados; y (b) investigar posibles relaciones entre las categorías analizadas. Una búsqueda en las bases de datos scopus, Web of Science y pubmed, utilizando el término "mand*", combinado con los términos "autism", "developmental disabilit*" o "intellectual disabilit*", resultó, luego de aplicar los criterios de inclusión/exclusión, en la identificación de 176 artículos publicados hasta septiembre del 2020. La mayoría de los estudios se llevaron a cabo en escuelas, con niños con un repertorio verbal preexistente. Las vis y vds más comunes fueron el reforzamiento diferencial y estímulos de ayuda y la manipulación de la operación motivadora para enseñar el mando por ítem/información, y el entrenamiento de comunicación funcional para reducir conductas inadecuadas. La mayoría de los procedimientos de enseñanza demostraron ser al menos parcialmente efectivos para todas las vds evaluadas, siendo importante un análisis más detallado de las variaciones en estos resultados con relación a los repertorios preintervención de los participantes. Se sugiere que se necesitan más investigaciones de personas con comportamiento verbal ausente o limitado, y con jóvenes y adultos con tea

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder.

BACKGROUND: Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD. METHODS: DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association. RESULTS: Two CpG-sites presented with p-values below 1 × 10-05 in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes. CONCLUSION: This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

Early adversity as the prototype gene × environment interaction in mental disorders?

Childhood adversity (CA) as a significant stressor has consistently been associated with the development of mental disorders. The interaction between CA and genetic variants has been proposed to play a substantial role in disease etiology. In this review, we focus on the gene by environment (GxE) paradigm, its background and interpretation and stress the necessity of its implementation in psychiatric research. Further, we discuss the findings supporting GxCA interactions, ranging from candidate gene studies to polygenic and genome-wide approaches, their strengths and limitations. To illustrate potential underlying epigenetic mechanisms by which GxE effects are translated, we focus on results from FKBP5 × CA studies and discuss how molecular evidence can supplement previous GxE findings. In conclusion, while GxE studies constitute a valuable line of investigation, more harmonized GxE studies in large, deep-phenotyped, longitudinal cohorts, and across different developmental stages are necessary to further substantiate and understand reported GxE findings.

DNA-methylation dynamics across short-term, exposure-containing CBT in patients with panic disorder.

Interaction of genetic predispositions and environmental factors via epigenetic mechanisms have been hypothesized to play a central role in Panic Disorder (PD) aetiology and therapy. Cognitive Behavioral Therapy (CBT), including exposure interventions, belong to the most efficient treatments of PD although its biological mechanism of action remains unknown. For the first time, we explored the dynamics and magnitude of DNA-methylation and immune cell-type composition during CBT (n = 38) and the therapeutic exposure intervention (n = 21) to unravel their biological correlates and identify possible biomarkers of therapy success. We report transient regulation of the CD4 + T-Cells, Natural Killers cells, Granulocytes during exposure and a significant change in the proportions of CD4 + T cells, CD8 + T cells and B-Cells and Granulocytes during therapy. In an epigenome-wide association study we identified cg01586609 located in a CpG island and annotated to the serotonin receptor 3 A (HTR3A) to be differentially methylated during fear exposure and regulated at gene expression level with significant differences between remitters and non-remitters (p = 0.028). We moreover report cg01699630 annotated to ARG1 to undergo long lasting methylation changes during therapy (paired t test, genome-wide adj.p value = 0.02). This study reports the first data-driven biological candidates for epigenetically mediated effects of acute fear exposure and CBT in PD patients. Our results provide evidence of changes in the serotonin receptor 3 A methylation and expression during fear exposure associated with different long-term CBT trajectories and outcome, making it a possible candidate in the search of markers for therapy success. Finally, our results add to a growing body of evidence showing immune system changes associated with PD.

Cutaneous adverse events to systemic antineoplastic therapies: a retrospective study in a public oncologic hospital

Abstract Background: Mucocutaneous adverse events are common during anticancer treatment, with variable consequences for the patient and their therapeutic regimen. Objective: To evaluate the most common adverse events, as well as the drugs associated with their appearance and the consequences for cancer treatment. Methods: A retrospective study was carried out through the analysis of patients treated at the Clinical Dermatology Unit of a public oncologic hospital. Results: A total of 138 patients with 200 adverse events were evaluated. The most commonly identified adverse events were nail and periungual changes (20%), papulopustular eruptions (13%), acneiform eruptions (12%), hand-foot syndrome (6.5%), hand-foot skin reaction (6%), and xerosis (6%). The most frequently associated antineoplastic treatment groups were classical chemotherapy (46.2%), target therapy (32.3%), and other non-antineoplastic drugs used in neoplasia protocols (16.5%). Of the total number of patients, 17.4% had their treatment suspended or changed due to a dermatological adverse event. Study limitations: Retrospective study and analysis of patients who were referred for specialized dermatological examination only, not allowing the assessment of the actual incidence of adverse events. Conclusion: A wide variety of dermatological manifestations are secondary to antineoplastic treatment with several different drugs resulting, not rarely, in the interruption or modification of therapeutic regimens.

Cutaneous adverse events to systemic antineoplastic therapies: a retrospective study in a public oncologic hospital.

BACKGROUND: Mucocutaneous adverse events are common during anticancer treatment, with variable consequences for the patient and their therapeutic regimen. OBJECTIVE: To evaluate the most common adverse events, as well as the drugs associated with their appearance and the consequences for cancer treatment. METHODS: A retrospective study was carried out through the analysis of patients treated at the Clinical Dermatology Unit of a public oncologic hospital. RESULTS: A total of 138 patients with 200 adverse events were evaluated. The most commonly identified adverse events were nail and periungual changes (20%), papulopustular eruptions (13%), acneiform eruptions (12%), hand-foot syndrome (6.5%), hand-foot skin reaction (6%), and xerosis (6%). The most frequently associated antineoplastic treatment groups were classical chemotherapy (46.2%), target therapy (32.3%), and other non-antineoplastic drugs used in neoplasia protocols (16.5%). Of the total number of patients, 17.4% had their treatment suspended or changed due to a dermatological adverse event. STUDY LIMITATIONS: Retrospective study and analysis of patients who were referred for specialized dermatological examination only, not allowing the assessment of the actual incidence of adverse events. CONCLUSION: A wide variety of dermatological manifestations are secondary to antineoplastic treatment with several different drugs resulting, not rarely, in the interruption or modification of therapeutic regimens.

Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation.

Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.

Taxane-induced scleroderma. Report of two cases.

Taxanes are a class of chemotherapeutic agents with common associated dermatologic adverse events, such as skin hyperpigmentation, hand-foot skin syndrome, paronychia and onycholysis. Taxane-induced scleroderma is rare. Few cases with skin findings resembling systemic sclerosis, have been reported after the administration of these agents. We report two cases with stage IV breast cancer, aged 66 and 71 years, who developed sclerodermic skin lesions in their extremities after starting treatment with placlitaxel and nabplaclitaxel respectively.

The pediatric buccal epigenetic clock identifies significant ageing acceleration in children with internalizing disorder and maltreatment exposure.

BACKGROUND: Studies reporting accelerated ageing in children with affective disorders or maltreatment exposure have relied on algorithms for estimating epigenetic age derived from adult samples. These algorithms have limited validity for epigenetic age estimation during early development. We here use a pediatric buccal epigenetic (PedBE) clock to predict DNA methylation-based ageing deviation in children with and without internalizing disorder and assess the moderating effect of maltreatment exposure. We further conduct a gene set enrichment analysis to assess the contribution of glucocorticoid signaling to PedBE clock-based results. METHOD: DNA was isolated from saliva of 158 children [73 girls, 85 boys; mean age (SD) = 4.25 (0.8) years] including children with internalizing disorder and maltreatment exposure. Epigenetic age was estimated based on DNA methylation across 94 CpGs of the PedBE clock. Residuals of epigenetic age regressed against chronological age were contrasted between children with and without internalizing disorder. Maltreatment was coded in 3 severity levels and entered in a moderation model. Genome-wide dexamethasone-responsive CpGs were derived from an independent sample and enrichment of these CpGs within the PedBE clock was identified. RESULTS: Children with internalizing disorder exhibited significant acceleration of epigenetic ageing as compared to children without internalizing disorder (F1,147 = 6.67, p = .011). This association was significantly moderated by maltreatment severity (b = 0.49, 95% CI [0.073, 0.909], t = 2.322, p = .022). Children with internalizing disorder who had experienced maltreatment exhibited ageing acceleration relative to children with no internalizing disorder (1-2 categories: b = 0.50, 95% CI [0.170, 0.821], t = 3.008, p = .003; 3 or more categories: b = 0.99, 95% CI [0.380, 1.593], t = 3.215, p = .002). Children with internalizing disorder who were not exposed to maltreatment did not show epigenetic ageing acceleration. There was significant enrichment of dexamethasone-responsive CpGs within the PedBE clock (OR = 4.36, p = 1.65*10-6). Among the 94 CpGs of the PedBE clock, 18 (19%) were responsive to dexamethasone. CONCLUSION: Using the novel PedBE clock, we show that internalizing disorder is associated with accelerated epigenetic ageing in early childhood. This association is moderated by maltreatment severity and may, in part, be driven by glucocorticoids. Identifying developmental drivers of accelerated epigenetic ageing after maltreatment will be critical to devise early targeted interventions.

Mycosis fungoides and Sézary syndrome: focus on the current treatment scenario

Abstract Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by infiltration of the skin by mature malignant T cells. Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, accounting for more than 60% of cases. Mycosis fungoides in the early-stage is generally an indolent disease, progressing slowly from some patches or plaques to more widespread skin involvement. However, 20% to 25% of patients progress to advanced stages, with the development of skin tumors, extracutaneous spread and poor prognosis. Treatment modalities can be divided into two groups: skin-directed therapies and systemic therapies. Therapies targeting the skin include topical agents, phototherapy and radiotherapy. Systemic therapies include biological response modifiers, immunotherapies and chemotherapeutic agents. For early-stage mycosis fungoides, skin-directed therapies are preferred, to control the disease, improve symptoms and quality of life. When refractory or in advanced-stage disease, systemic treatment is necessary. In this article, the authors present a compilation of current treatment options for mycosis fungoides and Sézary syndrome.