The time for new biomarkers in mycosis fungoides/Sézary syndrome is here

CRUE-CSIC (Acuerdos Transformativos 2021)Depto. de MedicinaFac. de MedicinaTRUESao Paulo Research FoundationNational Council of Technological and Scientific Developmentpu

Collagenase nanocapsules: An approach to fibrosis treatment

Fibrosis is a common lesion in different pathologic diseases and defined by the excessive accumulation ofcollagen. Different approaches have been used to treat different conditions characterized by fibrosis. TheFDA and EMA approved the use of collagenase to treat palmar fibromatosis (Dupuytren’s contracture).The EMA approved additionally its use in severe Peyronie’s disease, but it has been used off label in otherconditions [1,2]. The approved treatment includes up to three (in palmar fibromatosis) or up to eight (inpenile fibromatosis) injections followed by finger extension or penile modeling procedures, typicallycausing severe pain. Frequent single injections are adequate to treat palmar fibromatosis [3]. The needto repeatedly inject doses of this enzyme can be due to the labile nature of collagenase, which exhibitsa complete activity loss after a short period of time. This study presents a novel strategy to manage thisenzyme based on the synthesis of polymeric nanocapsules that contain collagenase encapsulated withintheir matrix. These nanocapsules have been engineered for achieving a gradual release of the encapsu-lated enzyme for a longer time, which can be up to ten days. The efficacy of these nanocapsules has beentested in a murine model of local dermal fibrosis, and the results demonstrate a reduction in fibrosisgreater than that with the injection of free enzyme; this type of treatment showed a significant improve-ment compared to conventional therapy of free collagenase

Secondary Prevention of Cancer in the Older Individual

The incidence and the mortality of cancer increase with age. This article explores the possibility of decreasing cancerrelated mortality in the aged with secondary prevention of cancer deaths that entails early diagnosis of cancer through the screening of asymptomatic older individuals. We establish that screening of asymptomatic individuals should be based on physiologic rather than chronologic age that may be estimated from a comprehensive geriatric assessment and possibly with the utilization of biologic markers of aging. It is reasonable to offer some form of screening for lung and colorectal cancer to individuals with a life expectancy of at least five years and screening for breast and prostate cancer to women and men respectively with a life expectancy of at least ten years. The ideal number of screening sessions and the ideal interval between screening sessions is unestablished. The aging of the population, the diversity of the older population, the development of new and more sensitive screening interventions, the discovery of new biologic markers of cancer and age represent the main challenges in studying the value of cancer screening in the aged. Probably the most reliable information may be obtained from rapid-learning databases in which information related to each person's physiologic age is included. Worldwide, the incidence and prevalence of cancer increase with age [1]. In the meantime the risk of cancer-related mortality increases with age at diagnosis [2-4]. As the world population is aging, cancer in the older person is an ever more common problem, and the reduction of cancer deaths in older individuals represents the most urgent goal of cancer control. In this article we explore secondary cancer prevention as representing a strategy to reduce the risk of mortality in the aged.This hypothesis is based on four considerations: i. Several studies showed that the practice of screening asymptomatic individuals for cancer becomes less common with the aging of the population [5]. ii. The average life expectancy of the Western population is rapidly increasing1. Consequently the benefits of early detection of cancer that emerges several years after diagnosis may be present even for those undergoing screening at an advanced age. iii. New forms of cancer treatment, including minimally invasive surgery [6], stereotactic radio surgery [7], and targeted systemic therapy [8], are associated with decreased risk of complications. They may be safely utilized in individuals with limited tolerance of stress who might be hurt by more aggressive treatments. It is now possible to personalize cancer screening according to individual life expectancy and tolerance of stress, as the estimate of a person's physiologic age is becoming more precise [1,9]. After reviewing the principles and the effectiveness of cancer screening and early detection, this article will explore the benefits and risks of secondary cancer prevention in older individuals. In particular we will review the current evidence and the limitations of previous clinical trials. At the end we will propose a conceptual framework to guide the screening of older individuals for cancer, and we will propose a research agenda

UVA-degradable Collagenase Nanocapsules as a potential treatment for fibrotic disease.

Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases

Live imaging of neolymphangiogenesis identifies acute antimetastatic roles of dsRNA mimics.

Long-range communication between tumor cells and the lymphatic vasculature defines competency for metastasis in different cancer types, particularly in melanoma. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here, we exploit immunocompetent and immunodeficient mouse models for live imaging of Vegfr3-driven neolymphangiogenesis, as a versatile platform for drug screening in vivo. Spatiotemporal analyses of autochthonous melanomas and patient-derived xenografts identified double-stranded RNA mimics (dsRNA nanoplexes) as potent inhibitors of neolymphangiogenesis, metastasis, and post-surgical disease relapse. Mechanistically, dsRNA nanoplexes were found to exert a rapid dual action in tumor cells and in their associated lymphatic vasculature, involving the transcriptional repression of the lymphatic drivers Midkine and Vegfr3, respectively. This suppressive function was mediated by a cell-autonomous type I interferon signaling and was not shared by FDA-approved antimelanoma treatments. These results reveal an alternative strategy for targeting the tumor cell-lymphatic crosstalk and underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers.The authors thank previous and present colleagues in the CNIO Melanoma Group, particularly Damia Tormo and Lisa Osterloh for help and support at the initial stages of this study; Jose A Esteban (CSIC-UAM) for critical reading of this manuscript; Lionel Larue (INSERM; France) and Martin McMahon (Hunstman Cancer Center, USA) for the Tyr:CreERT2 and BrafCA mouse strains, respectively; and Ignacio Melero at Hospital Clinico, Pamplona, Spain, for Ifnar1-deficient mice. The authors thank Isabel Blanco, Soraya Ruiz, and Virginia Granda (CNIO-Animal Facility Unit), Diego Megias (CNIO-Confocal Unit), and Eduardo Jose Caleiras and Patricia Gonzalez (CNIO-Histopathology Unit) for technical assistance. M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2017-89533-R), the Asociacion Espanola Contra el Cancer (AECC), Fundacion La Caixa, and an Established Investigator Award by the Melanoma Research Alliance (MRA). D.O. is funded by grants from the Spanish Ministry of Health (AES-PIS PI18/1057) and "Beca Leonardo a Investigadores y Creadores Culturales 2018 de la Fundacion BBVA". The CNIO Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019. S.O. is also supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness (BFU2015-71376-R).S

Association of APOA5 and APOC3 genetic polymorphisms with severity of hypertriglyceridemia in patients with cutaneous T-Cell lymphoma treated with bexarotene

Importance: hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives: to analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants: this case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures: primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results: among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance: these results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile

MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients

European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome - Update 2017

In order to provide a common standard for the treatment of mycosis fungoides (MF) and Sezary syndrome (SS), the European Organisation for Research and Treatment of Cancer-Cutaneous Lymphoma Task Force (EORTC-CLTF) published in 2006 its consensus recommendations for the stage-adapted selection of management options for these neoplasms. Since then, the understanding of the pathophysiology and epidemiology of MF/SS has advanced, the staging system has been revised, new outcome data have been published and novel treatment options have been introduced. The purpose of the present document is to update the original recommendations bearing in mind that there are still only a limited number of controlled studies to support treatment decisions for MF/SS and that often treatment is determined by institutional experience and availability. This consensus on treatment recommendations was established among the authors through a series of consecutive consultations in writing and a round of discussion. Recommended treatment options are presented according to disease stage, whenever possible categorised into first-and second-line options and supported with levels of evidence as devised by the Oxford Centre for Evidence-Based Medicine (OCEBM). Skin-directed therapies are still the most appropriate option for early-stage MF, and most patients can look forward to a normal life expectancy. For patients with advanced disease, prognosis is still grim, and only for a highly selected subset of patients, prolonged survival can be achieved with allogeneic stem cell transplantation (alloSCT). There is a high need for the development and investigation in controlled clinical trials of treatment options that are based on our increasing understanding of the molecular pathology of MF/SS. (C) 2017 The Authors. Published by Elsevier Ltd.Peer reviewe

First-line treatment in lymphomatoid papulosis: a retrospective multicentre study

Background: Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. Aim: To assess the daily clinical practice approach to LyP and the response to first-line treatments. Methods: This was a retrospective study enrolling 252 patients with LyP. Results: Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. Conclusions: Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse