Cryosurgery and 5-Fluorouracil Combination Therapy for Treatment of Bowen's Disease and Superficial Basal Cell Carcinoma.

BACKGROUND: Non-melanoma skin cancer (NMSC), which includes both Bowen's disease (BD) and superficial basal cell carcinoma (sBCC), is the most commonly diagnosed cancer in Canada. BD and sBCC are amenable to minimally invasive treatments however, large-scale studies assessing long-term outcomes are lacking, particularly regarding the timing and duration of non-invasive combination treatments. OBJECTIVE: Examine the clinical cure rate of BD and sBCC using a combination treatment consisting of a single cycle of cryotherapy followed by a three to four-week course of topical 5-fluorouracil (5-FU). METHODS: Retrospective chart review at a single center. Inclusion criteria included histology-proven sBCC or BD treated with either a combination protocol, cryosurgery, or 5-FU alone. RESULTS: 310 biopsy-confirmed cases of BD and 176 biopsy-confirmed cases of sBCC were analyzed. Of these, 229 cases of BD and 61 cases of sBCC were treated with cryosurgery and immediate 5-FU application, yielding a clearance rate of 90% and 86.9% at 6 months from initial treatment. CONCLUSION: Cryosurgery followed by immediate 5-FU use may be an effective mode of treatment for BD and sBCC, negating the need for invasive procedures and allowing for increased accessibility. Further studies with longer follow-up intervals, comparisons with other non-invasive treatments, and evidence of histologic cure are required. J Drugs Dermatol. 2023;22(12):1166-1171. doi:10.36849/JDD.7378.

GJB4 variants linked to skin disease exhibit a trafficking deficiency en route to gap junction formation that can be restored by co-expression of select connexins.

Epidermal keratinocytes are enriched with at least nine connexins that are key regulators of epidermal homeostasis. The role of Cx30.3 in keratinocytes and epidermal health became evident when fourteen autosomal dominant mutations in the Cx30.3-encoding GJB4 gene were linked to a rare and incurable skin disorder called erythrokeratodermia variabilis et progressiva (EKVP). While these variants are linked to EKVP, they remain largely uncharacterized hindering therapeutic options. In this study, we characterize the expression and functional status of three EKVP-linked Cx30.3 mutants (G12D, T85P, and F189Y) in tissue-relevant and differentiation-competent rat epidermal keratinocytes. We found that GFP-tagged Cx30.3 mutants were non-functional likely due to their impaired trafficking and primary entrapment within the endoplasmic reticulum (ER). However, all mutants failed to increase BiP/GRP78 levels suggesting they were not inducing an unfolded protein response. FLAG-tagged Cx30.3 mutants were also trafficking impaired yet occasionally exhibited some capacity to assemble into gap junctions. The pathological impact of these mutants may extend beyond their trafficking deficiencies as keratinocytes expressing FLAG-tagged Cx30.3 mutants exhibited increased propidium iodide uptake in the absence of divalent cations. Attempts to rescue the delivery of trafficking impaired GFP-tagged Cx30.3 mutants into gap junctions by chemical chaperone treatment were ineffective. However, co-expression of wild type Cx30.3 greatly enhanced the assembly of Cx30.3 mutants into gap junctions, although endogenous levels of Cx30.3 do not appear to prevent the skin pathology found in patients harboring these autosomal dominant mutations. In addition, a spectrum of connexin isoforms (Cx26, Cx30, and Cx43) exhibited the differential ability to trans-dominantly rescue the assembly of GFP-tagged Cx30.3 mutants into gap junctions suggesting a broad range of connexins found in keratinocytes may favourably interact with Cx30.3 mutants. We conclude that selective upregulation of compatible wild type connexins in keratinocytes may have potential therapeutic value in rescuing epidermal defects invoked by Cx30.3 EKVP-linked mutants.

Deriving Normative Data on 24-Hour Ambulatory Blood Pressure Monitoring for South Asian Children (ASHA): A Clinical Research Protocol.

BACKGROUND: The global prevalence of hypertension in children and adolescents has increased over the past 2 decades and is the strongest predictor of adult hypertension. South Asians have an increased prevalence of metabolic syndrome associated risk factors including abdominal obesity, diabetes, and hypertension. All these factors contribute to their increased cardiovascular disease burden. Accurate and early identification of hypertension in South Asian children is a necessary aspect of cardiovascular disease prevention. Ambulatory blood pressure monitoring (ABPM) is considered the gold-standard for pediatric blood pressure (BP) measurement. However, its utilization is limited due to the lack of validated normative reference data in diverse, multiethnic pediatric populations. OBJECTIVE: The primary objective is to establish normative height-sex and age-sex-specific reference values for 24-h ABPM measurements among South Asian children and adolescents (aged 5-17 years) in Ontario and British Columbia, Canada. Secondary objectives are to evaluate differences in ABPM measurements by body mass index classification, to compare our normative data against pre-existing data from German and Hong Kong cohorts, and to evaluate relationships between habitual movement behaviors, diet quality, and ABPM measurements. DESIGN: Cross-sectional study, quasi-representative sample. SETTING: Participants will be recruited from schools, community centers, and places of worship in Southern Ontario (Greater Toronto and Hamilton area, including the Peel Region) and Greater Vancouver, British Columbia. PARTICIPANTS: We aim to recruit 2113 nonoverweight children (aged 5-17 years) for the primary objective. We aim to recruit an additional 633 overweight or obese children to address the secondary objectives. MEASUREMENTS: Ambulatory BP monitoring measurements will be obtained using Spacelabs 90217 ABPM devices, which are validated for pediatric use. The ActiGraph GT3X-BT accelerometer, which has also been validated for pediatric use, will be used to obtain movement behavior data. METHODS: Following recruitment, eligible children will be fitted with 24-h ABPM and physical activity monitors. Body anthropometrics and questionnaire data regarding medical and family history, medications, diet, physical activity, and substance use will be collected. Ambulatory BP monitoring data will be used to develop height-sex- and age-sex-specific normative reference values for South Asian children. Secondary objectives include evaluating differences in ABPM measures between normal weight, overweight and obese children; and comparing our South Asian ABPM data to existing German and Hong Kong data. We will also use compositional data analysis to evaluate associations between a child's habitual movement behaviors and ABPM measures. LIMITATIONS: Bloodwork will not be performed to facilitate recruitment. A non-South Asian comparator cohort will not be included due to feasibility concerns. Using a convenience sampling approach introduces the potential for selection bias. CONCLUSIONS: Ambulatory BP monitoring is a valuable tool for the identification and follow-up of pediatric hypertension and overcomes many of the limitations of office-based BP measurement. The development of normative ABPM data specific to South Asian children will increase the accuracy of BP measurement and hypertension identification in this at-risk population, providing an additional strategy for primary prevention of cardiovascular disease.

CONTEXTE: La prévalence mondiale de l'hypertension chez les enfants et les adolescents a augmenté au cours des deux dernières décennies et constitue le plus important facteur prédictif de l'hypertension chez les adultes. Le syndrome métabolique associé aux facteurs de risque que sont l'obésité abdominale, le diabète et l'hypertension est plus prévalent chez les personnes d'origine sud-asiatique. Tous ces facteurs contribuent à une charge de morbidité cardiovasculaire accrue pour ces personnes. Le dépistage précis et précoce de l'hypertension chez les enfants d'Asie du Sud est un aspect incontournable de la prévention des maladies cardiovasculaires. Le monitoring ambulatoire de la pression artérielle (MAPA) est considéré comme la norme pour la mesure de la pression artérielle chez les enfants. Son utilization est toutefois limitée en raison de l'absence de références normatives validées dans des populations pédiatriques diversifiées et multiethniques. OBJECTIFS: L'objectif principal est d'établir des valeurs de référence normatives taille-sexe et âge-sexe pour les mesures de MAPA sur 24 heures chez les enfants et les adolescents d'origine sud-asiatique (âgés de 5-17 ans) de l'Ontario et de Colombie-Britannique (Canada). Les objectifs secondaires sont : 1) d'évaluer les différences dans les mesures de MAPA selon une classification basée sur l'indice de masse corporelle; 2) de comparer nos données normatives aux données préexistantes tirées de cohortes d'Allemagne et de Hong Kong, et 3) d'évaluer les relations entre les comportements actifs habituels, la qualité de l'alimentation et les mesures de MAPA. TYPE D'ÉTUDE: Étude transversale avec échantillon quasi représentatif. CADRE: Les participants seront recrutés dans des écoles, des centers communautaires et des lieux de culte du sud de l'Ontario (région du Grand Toronto et de Hamilton, y compris la région de Peel) et du Grand Vancouver en Colombie-Britannique. SUJETS: Nous souhaitons recruter 2113 enfants (5 à 17 ans) ne présentant pas de surpoids pour l'objectif principal. Et 633 enfants en surpoids ou obèses pour les objectifs secondaires. MESURES: Les mesures de MAPA seront obtenues à l'aide d'appareils Spacelabs 90217 validés pour un usage pédiatrique. L'accéléromètre ActiGraph GT3X-BT, également validé pour un usage pédiatrique, sera utilisé pour colliger des données sur le comportement actif. MÉTHODOLOGIE: Après le recrutement, les enfants admissibles seront équipés d'un appareil de MAPA pour 24 heures et de moniteurs d'activité physique. Les caractéristiques anthropométriques et les données d'un questionnaire portant sur les antécédents médicaux et familiaux, la médication, l'alimentation, l'activité physique et la consommation de substances seront recueillies. Les données de MAPA seront utilisées pour établir des valeurs de référence normatives taille-sexe et âge-sexe pour les enfants d'Asie du Sud. Les objectifs secondaires comprennent l'évaluation des différences dans les mesures de MAPA selon que les enfants ont un poids normal, un surpoids ou sont obèses, et la comparaison de nos données de MAPA pour des enfants d'Asie du Sud avec les données existantes en Allemagne et à Hong Kong. Nous procèderons également à l'analyze de composition des données afin d'évaluer les relations entre les comportements actifs habituels de l'enfant et les mesures de MAPA. LIMITES: Pour faciliter le recrutement, les analyses sanguines ne seront pas effectuées. Aucune cohorte de comparaison constituée de sujets non originaires d'Asie du Sud ne sera incluse en raison de problèmes de faisabilité. L'emploi d'une approche d'échantillonnage de commodité introduit un possible biais de sélection. CONCLUSION: Le MAPA est un outil précieux pour le dépistage et le suivi de l'hypertension pédiatrique et elle permet de surmonter plusieurs des limites de la mesure de la PA en cabinet. L'établissement de références normatives de MAPA spécifiques aux enfants d'Asie du Sud permettra d'accroître la précision de la mesure de la PA et le dépistage de l'hypertension dans cette population à risque, fournissant ainsi une stratégie supplémentaire pour la prévention primaire des maladies cardiovasculaires.

Is There A Causal Relationship between Childhood Obesity and Acute Lymphoblastic Leukemia? A Review.

Childhood obesity is a growing epidemic with numerous global health implications. Over the past few years, novel insights have emerged about the contribution of adult obesity to cancer risk, but the evidence base is far more limited in children. While pediatric patients with acute lymphoblastic leukemia (ALL) are at risk of obesity, it is unclear if there are potential causal mechanisms by which obesity leads to ALL development. This review explores the endocrine, metabolic and immune dysregulation triggered by obesity and its potential role in pediatric ALL's genesis. We describe possible mechanisms, including adipose tissue attraction and protection of lymphoblasts, and their impact on ALL chemotherapies' pharmacokinetics. We also explore the potential contribution of cytokines, growth factors, natural killer cells and adipose stem cells to ALL initiation and propagation. While there are no current definite causal links between obesity and ALL, critical questions persist as to whether the adipose tissue microenvironment and endocrine actions can play a causal role in childhood ALL, and there is a need for more research to address these questions.