The PROVe study: US real-world experience with chlormethine/mechlorethamine gel in combination with other therapies for patients with mycosis fungoides cutaneous T-cell lymphoma

BACKGROUND: Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking. OBJECTIVE: Our objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting. METHODS: This prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA-IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire. RESULTS: In total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores. CONCLUSIONS: This real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life

Aging Alters Functionally Human Dermal Papillary Fibroblasts but Not Reticular Fibroblasts: A New View of Skin Morphogenesis and Aging

Understanding the contribution of the dermis in skin aging is a key question, since this tissue is particularly important for skin integrity, and because its properties can affect the epidermis. Characteristics of matched pairs of dermal papillary and reticular fibroblasts (Fp and Fr) were investigated throughout aging, comparing morphology, secretion of cytokines, MMPs/TIMPs, growth potential, and interaction with epidermal keratinocytes. We observed that Fp populations were characterized by a higher proportion of small cells with low granularity and a higher growth potential than Fr populations. However, these differences became less marked with increasing age of donors. Aging was also associated with changes in the secretion activity of both Fp and Fr. Using a reconstructed skin model, we evidenced that Fp and Fr cells do not possess equivalent capacities to sustain keratinopoiesis. Comparing Fp and Fr from young donors, we noticed that dermal equivalents containing Fp were more potent to promote epidermal morphogenesis than those containing Fr. These data emphasize the complexity of dermal fibroblast biology and document the specific functional properties of Fp and Fr. Our results suggest a new model of skin aging in which marked alterations of Fp may affect the histological characteristics of skin

CD133 Positive Embryonal Rhabdomyosarcoma Stem-Like Cell Population Is Enriched in Rhabdospheres

Cancer stem cells (CSCs) have been identified in a number of solid tumors, but not yet in rhabdomyosarcoma (RMS), the most frequently occurring soft tissue tumor in childhood. Hence, the aim of this study was to identify and characterize a CSC population in RMS using a functional approach. We found that embryonal rhabdomyosarcoma (eRMS) cell lines can form rhabdomyosarcoma spheres (short rhabdospheres) in stem cell medium containing defined growth factors over several passages. Using an orthotopic xenograft model, we demonstrate that a 100 fold less sphere cells result in faster tumor growth compared to the adherent population suggesting that CSCs were enriched in the sphere population. Furthermore, stem cell genes such as oct4, nanog, c-myc, pax3 and sox2 are significantly upregulated in rhabdospheres which can be differentiated into multiple lineages such as adipocytes, myocytes and neuronal cells. Surprisingly, gene expression profiles indicate that rhabdospheres show more similarities with neuronal than with hematopoietic or mesenchymal stem cells. Analysis of these profiles identified the known CSC marker CD133 as one of the genes upregulated in rhabdospheres, both on RNA and protein levels. CD133+ sorted cells were subsequently shown to be more tumorigenic and more resistant to commonly used chemotherapeutics. Using a tissue microarray (TMA) of eRMS patients, we found that high expression of CD133 correlates with poor overall survival. Hence, CD133 could be a prognostic marker for eRMS. These experiments indicate that a CD133+ CSC population can be enriched from eRMS which might help to develop novel targeted therapies against this pediatric tumor

Efficacy and safety of single and multiple doses of pseudoephedrine in the treatment of nasal congestion associated with common cold

Background: Pseudoephedrine (60 mg) is widely used as an oral decongestant taken in tablet or syrup formulations every 4–6 hours for the treatment of nasal congestion associated with common cold and allergy. However, there are relatively few studies in the literature that have used objective measures of nasal airway resistance (NAR) to assess the efficacy of pseudoephedrine, and most studies use only a single dose of medication. The present study has the aims of studying the safety and efficacy of a new pseudoephedrine formulation after single and multiple doses in patients with URTI. Methods: The study was a double-blind, randomized, parallelgroup, placebo-controlled trial conducted over three study days at a single center. Patients suffering from nasal congestion associated with common cold were recruited and total NAR was measured by the technique of posterior rhinomanometry. NAR and subjective scores of nasal congestion were measured at baseline and after dosing with study medication, every hour over a four-hour period on day 1 after a single dose, and on day 3 after multiple doses of medication. Subjective scores of congestion/stuffiness were also made as a summary score at the end of each day of treatment. Results: Two hundred and thirty-eight patients with nasal congestion associated with acute upper respiratory tract infection (URTI), mean age 20 years, were recruited to the study and received treatment. After a single dose on day 1 the pseudoephedrine group had a statistically significant lower area under the NAR curve than placebo (p = 0.006) for the primary efficacy variable area under the NAR curve from 0–3 hours (NAR AUC 0–3h), and similarly for the secondary efficacy variable NAR AUC 0–4h (p = 0.001). On day three after multiple doses, the pseudoephedrine group had a statistically significant lower NAR AUC 0–3h and AUC 0–4h than placebo (p < 0.001), On day 1, the pseudoephedrine group had significantly lower subjective scores for congestion than placebo visual analog scale (VAS) AUC 0–3h (p = 0.029) and similarly for VAS AUC 0–4h (p = 0.021). On day 3, the differences in subjective scores were not significantly different. The mean decrease from baseline of the summary score for congestion/stuffiness over the duration of the study was greater in the pseudoephedrine group compared to the placebo group (p = 0.016). On average, heart rate was between two and four beats per minute greater in the pseudoephedrine group compared to placebo. Five adverse events were reported in both treatment groups and these were deemed to be unrelated to treatment. Conclusion: The results demonstrate that pseudoephedrine is a safe and effective treatment for nasal congestion associated with URTI. The results from the laboratory study on day 1 demonstrate by both objective and subjective measures of nasal congestion that a single dose of 60 mg pseudoephedrine is superior to placebo treatment. Support for the decongestant efficacy of multiple doses of pseudoephedrine is provided by objective measures on day 3 and subjective measures made over three days, but not by the VAS scores on day 3

Property rights and contractual approach to sustainable development

Sustainable development is argued to exist in weak and strong versions. Although the use of a property rights and contractual approach has been well understood in the case of weak sustainable development, the approach has been virtually ignored in the strong version. This paper formulates a property rights and contractual approach for the strong version of sustainable development. By reference to an analytical model and examples from Hong Kong and Taiwan, a Schumpeterian process and the institution of resource entitlements are shown to be the necessary ingredients to promote the strong version of sustainable development